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  • Electronic Resource  (742)
  • Loose Leaf
  • 1990-1994  (742)
  • 1991  (742)
  • Biochemistry and Biotechnology  (742)
  • 1
    Electronic Resource
    Electronic Resource
    Assignment of the nucleotide binding sites and the mechanism of substrate inhibition of Escherichia coli adenylate kinase (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 28-36 
    Details
    ISSN: 0887-3585
    Keywords: site-directed mutagenesis ; ATP and AMP binding sites ; tryptophan fluorescence ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Site-directed mutagenesis of key amino acids of adenylate kinase has been used to suggest a new model for the location of the AMP and ATP binding sites. Phe-86 and Tyr-133, which are in close contact with the inhibitor Ap5A according to previous crystallographic results, have been independently changed to tryptophan and other amino acids. The Phe-86→Trp mutant had a 3- to 6-fold change in the Km for ATP and a 44-fold increase in the Km for AMP with a simultaneous loss of AMP substrate inhibition. Thus Phe-86 is probably in close contact with bound AMP. The Tyr-133→Trp mutant showed no large effects on enzyme kinetics and suggests that the previous assignment of Ap5A occupying natural adenosine binding sites is probably incorrect. A temperature-sensitive Leu-107→Gln mutant showed a 6-fold decrease in the Km for ATP and no effect on AMP binding, suggesting that this amino acid is near the ATP binding site.Changes in the fluorescence of single tryptophan-containing mutant enzymes provided specific information about AMP and ATP binding. The fluorescence results are consistent with the kinetic studies, and also suggest that AMP substrate inhibition is caused by the formation of an abortive complex that prevents the release of product.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090105
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  • 2
    Electronic Resource
    Electronic Resource
    Erratum (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 79-79 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Additional Material: 1 Tab.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090109
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  • 3
    Electronic Resource
    Electronic Resource
    Distribution and complementarity of hydropathy in mutisunit proteins (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 37-55 
    Details
    ISSN: 0887-3585
    Keywords: protein-protein interactions ; intersubunit binding ; hydropathy ; hydropathy complementarity ; protein interfaces ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A survey of 40 multisubunit proteins and 2 protein-protein complexes was performed to assay quantitatively the distribution of hydropathy among the exterior surface, interior, contact surface, and noncontact exterior surface of the isolated subunits. We suggest a useful way to present this distribution by using a “hydropathy level diagram.” Additionally, we have devised a function called “hydropathy complementarity” to quantitate the degree to which interacting surfaces have matching hydropathy distributions. Our survey revealed the following patters: (1) The difference in hydropathy between the interior and exterior of subunits is a fairly invariant quantity. (2) On average, the hydropathy of the contact surface is higher than that of the exterior surface, but is not greater than that of the protein as a whole. There was variation, however, among the proteins. In some instances, the contact surface was more hydrophilic than the noncontact exterior, and in a few cases the contact surface was as hydrophobic as the protein interior. (3) The average interface manifests significant hydropathy complementarity, signifying that proteins interact by placing hydrophobic centers of one surface against hydrophobic centers of the other surface, and by similarly matching hydrophilic centers. As a measure of recognition and specificity, hydropathy complementarity could be a useful tool for predicting correct docking of interacting proteins. We suggest that high hydropathy complementarity is associated with static inflexible interactions. (4) We have found that some subunits that bind predominantly through hydrophilic forces, such as hydrogen bonds, ionic pairs, and water and metal bridges, are involved in dynamic quaternary organization and allostery.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090106
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  • 4
    Electronic Resource
    Electronic Resource
    Phospholipase A2 at the bilayer interface (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 229-239 
    Details
    ISSN: 0887-3585
    Keywords: phospholipase A2 ; interfacial catalysis ; interfacial activation ; resonance energy transfer ; lipid-protein interaction ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Interfacial catalysis is a necessary consequence for all enzymes that act on amphipathic substrates with a strong tendency to form aggregates in aqueous dispersions. In such cases the catalytic event occurs at the interface of the aggregated substrate, the overall turnover at the interface is processive, and it is influenced the molecular organization and dynamics of the interface. Such enzymes can access the substrate only at the interface because the concentration of solitary monomers of the substrate in the aqueous phase is very low. Moreover, the microinterface between the bound enzyme and the organized substrate not only facilitates formation of the enzyme-substrate complex, but a longer residence time of the enzyme at the substrate interface also promotes high catalytic processivity.Binding of the enzyme to the substrate interface as an additional step in the overall catalytic turnover permits adaptation of the Michaelis-Menten formalism as a basis to account for the kinetics of interfacial catalysis. As shown for the action of phospholipase A2 on bilayer vesicles, binding equilibrium has two extreme kinetic consequences. During catalysis in the scooting mode the enzyme does not leave the surface of the vesicle to which it is bound. On the other hand, in the hopping mode the absorption and desorption steps are a part of the catalytic turnover.In this minireview we elaborate on the factors that control binding of pig pancreatic phospholipase A2 to the bilayer interface. Binding of PLA2 to the interface occurs through ionic interactions and is further promoted by hydrophobic interactions which probably occur along a face of the enzyme, with a hydrophobic collar and a ring of cationic residues, through which the catalytic site is accessible to substrate molecules in the bilayer. An enzyme molecule binds to the surface occupied by about 35 lipid molecules with an apparent dissociation constant of less than 0.1 pM for the enzyme on anionic vesicles compared to 10 mM on zwitterionic vesicles. Results at hand also show that aggregation or acylation of the protein is not required for the high affinity binding or catalytic interaction at the interface.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090402
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  • 5
    Electronic Resource
    Electronic Resource
    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100101
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  • 6
    Electronic Resource
    Electronic Resource
    Electron redistribution on binding of a substrate to an enzyme: Folate and dihydrofolate reductase (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 217-224 
    Details
    ISSN: 0887-3585
    Keywords: protein-ligand interactions ; electron density ; quantum mechanics ; local density functional theory ; charge polarization ; enzymatic reaction ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The migration of electron density of a substrate (folate) on binding to an enzyme (dihydrofolate reductase) is studied by a quantum-mechanical method originally developed in solid state physics. A significant polarization of the substrate is induced by the enzyme, toward the transition state of the enzymatic reaction, at the same time giving rise to “electronic strain energy” in the substrate and enhanced protein-ligand interactions. The spatial arrangement of protein charges that induces the polarization is identified and found to be structurally conserved for bacterial and vertebrate dihydrofolate reductases.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090307
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  • 7
    Electronic Resource
    Electronic Resource
    Hexamers of subunit II from Limulus hemocyanin (a 48-mer) have the same quaternary structure as whole Panulirus hemocyanin molecules (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 240-247 
    Details
    ISSN: 0887-3585
    Keywords: hemocyanin ; Limulus ; Panulirus ; horseshoe crab ; spiny lobster ; molecular replacement ; X-ray ; crystallography ; protein structure ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Hemocyanins are copper-containing proteins that transport oxygen in a variety of invertebrates. Considerable evidence has accumulated that arthropodan hemocyanins are multimers of a fundamental hexameric unit. X-Ray crystallographic structure determination has revealed that the hemocyanin molecule from the spiny lobster Panulirus interruptus is a single hexamer having 32 point group symmetry. Using crystals of subunit II, one of 8 polypeptide types comprising the octahexameric hemocyanin of the horseshoe crab Limulus polyphemus, and the molecular replacement method for crystallographic phase determination we show that subunit II forms assemblies with the same hexameric quaternary structure as the whole Panulirus hemocyanin molecule. Observation of the same hexameric motif in two widely separated species provides strong additional evidence that this quaternary structural unit is a universal building block of arthropodan hemocyanins.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090403
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  • 8
    Electronic Resource
    Electronic Resource
    Hydrophobic clustering in nonnative states of a protein: Interpretation of chemical shifts in NMR spectra of denatured states of lysozyme (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 248-266 
    Details
    ISSN: 0887-3585
    Keywords: protein folding ; unfolded state ; denatured state ; hydrophobic interactions ; ring current shift ; magnetization transfer NMR ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Chemical shifts of resonances of specific protons in the 1H NMR spectrum of thermally denatured hen lysozyme have been determined by exchange correlation with assigned native state resonances in 2D NOESY spectra obtained under conditions where the two states are interconverting. There are subtle but widespread deviations of the measured shifts from the values which would be anticipated for a random coil; in the case of side chain protons these are virtually all net upfield shifts and it is shown that this may be the averaged effect of interactions with aromatic rings in a partially collapsed denatured state. In a very few cases, notably that of two sequential tryptophan residues, it is possible to interpret these effects in terms of specific, local interresidue interactions. Generally, however, there is no correlation with either native state shift perturbations or with sequence proximity to aromatic groups. Diminution of most of the residual shift perturbations on reduction of the disulfide cross-links confirms that they are not simply effects of residues adjacent in the sequence. Similar effects of chemical denaturants, with the disulfides intact, demonstrate that the shift perturbations reflect an enhanced tendency to side chain clustering in the thermally denatured state. The temperature dependences of the shift perturbations suggest that this clustering is noncooperative and is driven by small, favorable enthalpy changes. While the extent of conformational averaging is clearly much greater than that observed for a homologous protein, α-lactalbumin, in its partially folded “molten globule” state, the results clearly show that thermally denatured lysozyme differs substantially from a random coil, principally in that it is partially hydrophobically collapsed.
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090404
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  • 9
    Electronic Resource
    Electronic Resource
    The adaptability of the active site of trypanosomal triosephosphate isomerase as observed in the crystal structures of three different complexes (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 50-69 
    Details
    ISSN: 0887-3585
    Keywords: TIM ; protein-ligand complexes ; water involvement in binding ; drug design ; active site structure ; sleeping sickness ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Crystals of triosephosphate isomerase from Trypanosoma brucei brucei have been used in binding studies with three competitive inhibitors of the enzyme's activity. Highly refined structures have been deduced for the complexes between trypanosomal triosephosphate isomerase and a substrate analogue (glycerol-3-phosphate to 2.2 Å), a transition state analogue (3-phosphonopropionic acid to 2.6 Å), and a compound structurally related to both (3-phosphoglycerate to 2.2 Å). The active site structures of these complexes were compared with each other, and with two previously determined structures of triosephosphate isomerase either free from inhibitor or complexed with sulfate. The comparison reveals three conformations available to the “flexible loop” near the active site of triosephosphate isomerase: open (no ligand), almost closed (sulfate), and fully closed (phosphate/phosphonate complexes). Also seen to be sensitive to the nature of the active site ligand is the catalytic residue Glu-167. The side chain of this residue occupies one of two discrete conformations in each of the structures so far observed. A “swung out” conformation unsuitable for catalysis is observed when sulfate, 3-phosphoglycerate, or no ligand is bound, while a “swung in” conformation ideal for catalysis is observed in the complexes with glycerol-3-phosphate or 3-phosphonopropionate. The water structure of the active site is different in all five structures. The results are discussed with respect to the triosephosphate isomerase structure function relationship, and with respect to an on-going drug design project aimed at the selective inhibition of glycolytic enzymes of T. brucei.
    Additional Material: 12 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100106
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  • 10
    Electronic Resource
    Electronic Resource
    Projection of monte carlo and molecular dynamics trajectories onto the normal mode axes: Human lysozyme (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 106-116 
    Details
    ISSN: 0887-3585
    Keywords: collective motion ; hinge bending motion ; normal mode analysis ; anharmonic motion ; low-frequency motion ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A method is presented to describe the internal motions of proteins obtained from molecular dynamics or Monte Carlo simulations as motions of normal mode variables. This method calculates normal mode variables by projecting trajectories of these simulations onto the axes of normal modes and expresses the trajectories as a linear combination of normal mode variables. This method is applied to the result of the molecular dynamics and the Monte Carlo simulations of human lysozyme. The motion of the lowest frequency mode extracted from the simulations represents the hinge bending motion very faithfully. Analysis of the obtained motions of the normal mode variables provides an explanation of the anharmonic aspects of protein dynamics as due first to the anharmonicity of the actual potential energy surface near a minimum and second to trans-minimum conformational changes.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100204
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  • 11
    Electronic Resource
    Electronic Resource
    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100301
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  • 12
    Electronic Resource
    Electronic Resource
    Cu(II)-Binding properties of a cytochrome c with a synthetic metal-binding site: His-X3-His in an α-helix (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 156-161 
    Details
    ISSN: 0887-3585
    Keywords: synthetic metalloproteins ; protein engineering ; iso-1-cytochrome c ; metal binding ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A metal-binding site consisting of two histidines positioned His-X3-His in an α-helix has been engineered into the surface of Saccharomyces cerevisiae iso-1-cytochrome c. The synthetic metal-binding cytochrome c retains its biological activity in vivo. Its ability to bind chelated Cu(II) has been characterized by partitioning in aqueous two-phase polymer systems containing a polymer-metal complex, Cu(II)IDA-PEG, and by metal-affinity chromatography. The stability constant for the complex formed between Cu(II)IDA-PEG and the cytochrome c His-X3-His site is 5.3 × 104 M-1, which corresponds to a chelate effect that contributes 1.5 kcal mol-1 to the binding energy. Incorporation of the His-X3-His site yields a synthetic metal-binding protein whose metal affinity is sensitive to environmental conditions that alter helix structure or flexibility.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100209
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  • 13
    Electronic Resource
    Electronic Resource
    Proline in α-helix: Stability and conformation studied by dynamics simulation (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 219-228 
    Details
    ISSN: 0887-3585
    Keywords: proline ; α-helix ; kinked α-helix ; molecular dynamics ; computer simulation ; peptide conformation stability ; protein conformational stability ; amino acid substitution ; protein architecture ; helix start/stop signal ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Free-energy simulations have been used to estimate the change in the conformational stability of short polyalanine α-helices when one of the alanines is replaced by a proline residue. For substituting proline in the middle of the helix the change in free energy of folding (ΔΔG°) was calculated as 14 kJ/mol (3.4 kcal/mol), in excellent agreement with the one available experimental value. The helix containing proline was found to be strongly kinked; the free energy for reducing the angle of the kink from 40° to 15° was calculated, and found to be small. A tendency to alternate hydrogen bonding schemes was observed in the proline-containing helix. These observations for the oligopeptide agree well with the observation of a range of kink angles (18-35°) and variety of hydrogen bonding schemes, in the rare instances where proline occurs in helices in globular proteins. For substituting proline at the N-terminus of the helix the change in free energy of folding (ΔΔG°) was calculated as -4 kJ/mol in the first helical position (N1) and +6 kJ/mol in the second helical position (N2). The observed frequent occurrence of proline in position N1 in α-helices in proteins therefore has its origin in stability differences of secondary structure. The conclusion reached here that proline may be a better helix former in position N1 than (even) alanine, and thus be a helix initiator may be testable experimentally by measurements of fraction helical conformation of individual residues in oligopeptides of appropriate sequence. The relevance of these results in regards to the frequent occurrence of proline-containing helices in certain membrane proteins is discussed.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100306
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  • 14
    Electronic Resource
    Electronic Resource
    Crystallographic refinement of ricin to 2.5 Å (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 240-250 
    Details
    ISSN: 0887-3585
    Keywords: ricin ; refinement ; molecular dynamics ; molecular models ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The plant cytotoxin ricin consists of two disulfide-linked chains, each of about 30,000 daltons. An initial model based on a 2.8 Å MIR electron density map has been refined against 2.5 Å data using rounds of hand rebuilding coupled with either a restrained least squares algorithm or molecular dynamics (XPLOR). The last model (9) has an R factor of 21.6% and RMS deviations from standard bond lengths and angles of 0.021 Å and 4.67°, respectively. Refinement required several peptide segments in the original model to be adjusted translationally along the electron density. A wide range of lesser changes were also made. The RMS deviation of backbone atoms between the original and model 9 was 1.89 Å. Molecular dynamics proved to be a very powerful refinement tool. However, tests showed that it could not replace human intervention in making adjustments such as local translations of the peptide chain. The R factor is not a completely satisfactory indicator of refinement progress; difference Fouriers, when observed carefully, may be a better monitor.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100308
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  • 15
    Electronic Resource
    Electronic Resource
    Exploration of disorder in protein structures by X-ray restrained molecular dynamics (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 340-358 
    Details
    ISSN: 0887-3585
    Keywords: ribonuclease A ; crambin ; conformational disorder ; protein crystallography ; simulated annealing ; X-ray refinement ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Conformational disorder in crystal structures of ribonuclease-A and crambin is studied by including two independent structures in least-squares optimizations against X-ray data. The optimizations are carried out by X-ray restrained molecular dynamics (simulated annealing refinement) and by conventional least-squares optimization. Starting from two identical structures, the optimizations against X-ray data lead to significant deviations between the two, with rms backbone displacements of 0.45 Å for refinement of ribonuclease at 1.53 Å resolution, and 0.31 Å for crambin at 0.945 Å. More than 15 independent X-ray restrained molecular dynamics runs have been carried out for ribonuclease, and the displacements between the resulting structures are highly reproducible for most atoms. These include residues with two or more conformations with significant dihedral angle differences and alternative hydrogen bonding, as well as groups of residues that undergo displacements that are suggestive of rigid-body librations. The crystallographic R-values obtained are ≈ 13%, as compared to 15.3% for a comparable refinement with a single structure. Least-squares optimization without an intervening restrained molecular dynamics stage is sufficient to reproduce most of the observed displacements. Similar results are obtained for crambin, where the higher resolution of the X-ray data allows for refinement of unconstrained individual anisotropic temperature factors. These are shown to be correlated with the displacements in the two-structure refinements.
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100407
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  • 16
    Electronic Resource
    Electronic Resource
    Thermodynamics of ligand binding and denaturation for his64 mutants of tissue plasminogen activator kringle-2 domain (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 35-44 
    Details
    ISSN: 0887-3585
    Keywords: microcalorimetry ; thermal stability ; lysine binding ; site-directed ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The contribution of His64 to the function and stability of tissue plasminogen activator (t-PA) kringle-2 domain (His244 in t-PA numbering) has been studied by using microcalorimetric methods to compare the ligand binding and thermal denaturation behavior of wild-type kringle-2 and mutants having His64 replaced with Tyr or Phe. This site was examined because modeling studies1 suggested that the His64 side chain could play an important role in ligand binding by forming an ion-pair with the carboxylate of the ligand, L-lysine. Kringle-2 domains were expressed by secretion of the 174-263 portion of t-PA in E. coli and purified as previously described for the wild-type domain.2 Both mutant proteins retain affinity for L-lysine, although reduced three- to four-fold relative to wild-type, demonstrating that His64 does not interact with the ligand carboxylate through an ion-pair interaction or by hydrogen bonding. The H64Y substitution does result in an altered specificity of the lysine binding site with the mutant domain having greatest affinity for a ligand of 6.8 Å chain length, whereas the wild-type domain prefers an 8.8 Å long ligand. For both wild-type and mutant, the binding of the optimal chain length ligand is dominated by enthalpic effects (ΔH = -6,000 to -7,000 cal/mol) and TΔS accounts for 〈 15% of ΔG. In addition, the H64Y mutant differs from wild-type in the effect of ligand α-amino group modification on binding affinity. Based on examination of the x-ray structure recently determined for wild-type kringle-2, the specificity changes accompanying the H64Y substitution probably result from changes in side chain interactions in the lysine binding site. Thermal denaturation experiments show that the H64Y mutant is also more stable than the wild-type protein with the difference in stabilization free energy (ΔΔG) equal to 2.7 kcal/mol at 25°C and pH 3. The increased stability of the mutant appears to be related to the difference in hydrophobicity between His and Tyr.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110105
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  • 17
    Electronic Resource
    Electronic Resource
    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110201
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  • 18
    Electronic Resource
    Electronic Resource
    Effect of urey-bradley-shimanouchi force field on the harmonic dynamics of proteins (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 120-132 
    Details
    ISSN: 0887-3585
    Keywords: normal mode analysis ; potential energy function ; Lys-15 ; Arg-17 residues ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A normal mode analysis of bovine pancreatic trypsin inhibitor is carried out by using a Urey-Bradley-Shimanouchi potential energy function. The density of vibrational states, the magnitudes, and time scales of the atomic fluctuations are compared with experimental and theoretical results obtained by the more commonly used potential energy functions. The atomic fluctuations of Lys-15 are subject to extensive considerations as this residue is buried in the trypsin specificity pocket. It is found that Arg-17 is likely to be of importance in order to understand the way BPTI binds on trypsin.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110205
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  • 19
    Electronic Resource
    Electronic Resource
    Asymmetric inclusion by de novo designed proteins: Fluorescence probe studies on amphiphilic α-helix bundles (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 133-141 
    Details
    ISSN: 0887-3585
    Keywords: fluorescence depolarization ; coiled-coil ; induced circular dichroism ; exciton chirality ; ANS ; acridine orange ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The inclusion feature and supersecondary structure of the de novo designed proteins which are constructed with several amphiphilic α-helices and flexible linkage parts were investigated with fluorescence probes. Five types of small proteins (or peptides) have been designed, which are composed of 2, 3, 4, 4, and 6 helices, respectively, and are linked with only linear junctions except for one of 4-helix proteins. All of these proteins have inclusion ability for hydrophobic fluorophores. Further, by the analysis of fluorescence polarization anisotropy, it was suggested that these proteins include guest molecules in compact helix bundles constructed with about 4 helices. Asymmetric inclusion of both monomer and stacked dimer of acridine orange derivatives was found by means of induced circular dichroism except for the 4-helix protein with cross-junction. The chirality of the included dimer proved to be in accordance with the chiral sense of α-helical coiled-coil. The 6-helix protein has especially high efficiency in inclusion for any fluorophores examined in this study and brings about a significant blue-shift of maximal emission for 8-anilino-1-naphthalenesulfonate.
    Additional Material: 11 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110206
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    Electronic Resource
    Electronic Resource
    Collective motions in proteins: A covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 205-217 
    Details
    ISSN: 0887-3585
    Keywords: molecular dynamics ; normal modes ; collective motions ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A method is described for identifying collective motions in proteins from molecular dynamics trajectories or normal mode simulations. The method makes use of the covariances of atomic positional fluctuations. It is illustrated by an analysis of the bovine pancreatic trypsin inhibitor. Comparison of the covariance and cross-correlation matrices shows that the relative motions have many similar features in the different simulations. Many regions of the protein, especially regions of secondary structure, move in a correlated manner. Anharmonic effects, which are included in the molecular dynamics simulations but not in the normal analysis, are of some importance in determining the larger scale collective motions, but not the more local fluctuations. Comparisons of molecular dynamics simulations in the present and absence of solvent indicate that the environment is of significance for the long-range motions.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110305
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  • 21
    Electronic Resource
    Electronic Resource
    Analysis of the steric strain in the polypeptide backbone of protein molecules (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 223-229 
    Details
    ISSN: 0887-3585
    Keywords: protein structure ; crystal structure ; dihedral angles ; cis peptides ; protein active sites ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The extent to which local strain is present in the polypeptide backbone of folded protein molecules has been examined. The occurrence of steric strain associated with nonproline cis peptide bonds and energetically unfavorable main chain dihedral angles can be identified reliably from the well ordered parts of high resolution, refined crystal structures. The analysis reveals that there are relatively few sterically strained features. Those that do occur are located overwhelmingly in regions concerned with function. We attribute this to the greater precision necessary for ligand binding and catalysis, compared with the requirements of satisfactory folding.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110307
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  • 22
    Electronic Resource
    Electronic Resource
    Crystallization and preliminary X-ray diffraction studies of human salivary α-amylase (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 230-232 
    Details
    ISSN: 0887-3585
    Keywords: parotid saliva ; enzyme ; crystals ; X-ray analysis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Nonglycosylated α-amylase, a major component of human parotid saliva, has been crystallized by the vapor diffusion technique using 2-methyl-2,4-pentanediol as the precipitant in the presence of CaCl2 at pH 9.0. The crystals are orthorhombic, space group P212121 with unit cell dimensions of a = 53.3, b = 75.8, and c = 138.1 Å. The asymmetric unit contains one amylase molecule. The solvent content is 54%. The crystals are stable to X-rays and diffract up to 2.8 Å and appear to be suitable for X-ray diffraction studies.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110308
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  • 23
    Electronic Resource
    Electronic Resource
    Protein-protein recognition analyzed by docking simulation (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 271-280 
    Details
    ISSN: 0887-3585
    Keywords: antigen-antibody recognition ; protease-inhibitor complexes ; simulated annealing ; energy refinement ; docking algorithm ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Antibody-lysozyme and protease-inhibitor complexes are reconstituted by docking lysozyme as a rigid body onto the combining site of the antibodies and the inhibitors onto the active site of the proteases. Simplified protein models with one sphere per residue are subjected to simulated annealing using a crude energy function where the attractive component is proportional to the interface area. The procedure finds clusters of orientations in which a steric fit between the two protein components is achieved over a large contact surface. With five out of six complexes, the native structure of the complexes determined by X-ray crystallography is among those retained. Docked complexes are then subjected to conformational energy refinement with full atomic detail. With Fab HyHEL 5 and lysozyme, a native-like complex has the lowest refined energy. It can also be retrieved when starting with the X-ray structure of free lysozyme. However, some non-native complexes cannot be rejected: they form large interfaces, have a large number of H-bonds, and few unpaired polar groups. While these are necessary features of protein-protein recognition, they are not sufficient in determining specificity.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110406
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  • 24
    Electronic Resource
    Electronic Resource
    Computer design of bioactive molecules: A method for receptor-based de novo ligand design (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 314-328 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The design of molecules to bind specifically to protein receptors has long been a goal of computer-assisted molecular design. Given detailed structural knowledge of the target receptor, it should be possible to construct a model of a potential ligand, by algorithmic connection of small molecular fragments, that will exhibit the desired structural and electrostatic complementarity with the receptor. However, progress in this area of receptorbased, de novo ligand design has been hampered by the complexity of the construction process, in which potentially huge numbers of structures must be considered. By limiting the scope of the structure-space examined to one particular class of ligands-namely, peptides and peptide-like compounds-the problem complexity has been reduced to the point that successful, de novo design is now possible. The methodology presented employs a large template set of amino acid conformations which are iteratively pieced together in a model of the target receptor. Each stage of ligand growth is evaluated according to a molecular mechanicsbased energy function, which considers van der Waals and coulombic interactions, internal strain energy of the lengtheining ligand, and desolvation of both ligand and receptor. The search space is managed by use of a data tree which is kept under control by pruning according to the energy evaluation. Ligands grown by this procedure are subjected to follow-up evaluation in which an approximate binding enthalpy is determined. This methodology has proven useful as a precise model-builder and has also shown the ability to design bioactive ligands.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110409
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  • 25
    Electronic Resource
    Electronic Resource
    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090101
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  • 26
    Electronic Resource
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    Design and synthesis of the pseudo-EF hand in calbindin D9K: Effect of amino acid substitutions in the α-helical regions (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 12-22 
    Details
    ISSN: 0887-3585
    Keywords: calbindin D9K ; pseudo-EF hand ; peptide synthesis ; peptide design ; calcium ; α-helix ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A series of 37-residue analogues of the pseudo-EF hand in bovine calbindin D9K has been synthesized by the solid phase method. In the presence of calcium an α-helical induction of up to 44% was observed for the peptide with the native sequence with a Kd for calcium binding of 0.35 mM. A number of amino acid substitutions have been carried out to study the packing of the two α-helices based on the crystal structure of the entire protein. Three strategies were employed: (1) replacement of the Leu residues, which in the crystal structure do not contribute to the hydrophobic interaction between the two helices, by Gln or Ala in order to control the orientation of the helix packing, (2) stabilization of the individual helix by introducing a Glu-…Lys+ salt bridge or by changing the N-terminal charge to compensate for the helix dipole moment, and (3) introduction of a disulfide bond between the two helices to help the packing of the helices.The mutants with the substitution of (Leu-30, Leu-32) to (Gln-30, Gln-32), (Gln-30, Ala-32), and (Ala-30, Ala-32) designed based on the strategy 1 do not show any affinity for calcium and have low α-helicity. The Leu-30 to Lys-30 mutant designed to form a salt bridge between the side chains of Glu-26 and Lys-30 has an apparent Kd for calcium of 6.8 mM. Kd of the N-terminal acetylated and succinylated mutants are 0.41 and 0.45 mM, respectively, and no increase in the α-helix content relative to that of the natural sequence peptide is observed. The disulfide containing mutants, namely Tyr-13, Leu-31 to Cys-31 and Tyr-13, Leu-31 to Cys-13, hCys-31, show apparent Kd values of 0.93 and 2.1 mM, respectively. The former mutant shows the highest α-helix content among the peptides studied in the presence and absence of calcium. While it is difficult to construct an isolated and rigid helix-loop-helix motif with peptides of this size, introduction of a disulfide bond proved to be effective for this purpose.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090103
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  • 27
    Electronic Resource
    Electronic Resource
    Rate of β-structure formation in polypeptides (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 23-27 
    Details
    ISSN: 0887-3585
    Keywords: polypeptides ; protein folding ; β-structure ; free energy barrier ; nucleation of folding ; rate-limiting step ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: An explanation is suggested for why a marginally stable β-structure folds extremely slowly; it is predicted that even a small increase in stability drastically accelerates β-folding. According to the theory, this folding is a first-order phase transition, and the rate-limiting step is nucleation. The rate-determining “nucleus” (transition state) is the smallest β-sheet that is sufficiently large to provide an overall free energy reduction during subsequent folding. If the stability of the β-structure is low, the nucleus is large and possesses a high free energy due to having a large perimeter. When the net stability of the final β-structure increases (due to either an increase of the β-sheet stability or a decrease in stability of the competing structures, e.g., α-helices), the size and energy of a nucleus decrease and the rate of folding increases exponentially. This must result in a fast folding of polypeptides enriched by β-forming residues (e.g., protein chains). The theory is developed for intramolecular β-structure, but it can also explain the overall features of intermolecular β-folding; it is applicable both to antiparallel and parallel β-sheets. The difference in folding of β-sheets, α-helices, and proteins is discussed.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090104
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  • 28
    Electronic Resource
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    Database of homology-derived protein structures and the structural meaning of sequence alignment (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 56-68 
    Details
    ISSN: 0887-3585
    Keywords: secondary structure ; tertiary structure ; residue conservation ; sequence variability ; sequence profile ; folding units ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The database of known protein three-dimensional structures can be significantly increased by the use of sequence homology, based on the following observations. (1) The database of known sequences, currently at more than 12,000 proteins, is two orders of magnitude larger than the database of known structures. (2) The currently most powerful method of predicting protein structures is model building by homology. (3) Structural homology can be inferred from the level of sequence similarity. (4) The threshold of sequence similarity sufficient for structural homology depends strongly on the length of the alignment. Here, we first quantify the relation between sequence similarity, structure similarity, and alignment length by an exhaustive survey of alignments between proteins of known structure and report a homology threshold curve as a function of alignment length. We then produce a database of homology-derived secondary structure of proteins (HSSP) by aligning to each protein of known structure all sequences deemed homologous on the basis of the threshold curve. For each known protein structure, the derived database contains the aligned sequences, secondary structure, sequence variability, and sequence profile. Tertiary structures of the aligned sequences are implied, but not modeled explicity. The database effectively increases the number of known protein structures by a factor of five to more than 1800. The results may be useful in assessing the structural significance of matches in sequence database searches, in deriving preferences and patterns for structure prediction, in elucidating the structural role of conserved residues, and in modeling three-dimensional detail by homology.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090107
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  • 29
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    Refined structure of melittin bound to perdeuterated dodeclylphoscholine micelles as studied by 2D-NMR and distance geometry calculation (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 81-89 
    Details
    ISSN: 0887-3585
    Keywords: 2D-NMR experiment ; distance geometry ; hydrogen bond ; side chain conformation ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: In our previous paper we reported the conformation of melittin bound to perdeuterated dodecylphosphocholine micelles as studied by 1H NMR experiment and distance geometry calculation. No hydrogen bonds were taken into consideration explicitly in the calculation. However, mostly α-helical conformations were obtained as results of the calculation even with no explicitly assumed hydrogen bonds. In the present paper we refined the distance geometry calculation by incorporating hydrogen bonds suggested by the previous calculation. As a result, we obtained the conformation of melittin, which was consistent with both NMR data and the additional hydrogen bonding data. The α-helical rod in the refined conformation also has a kink at Thr-11 and Gly-12, but its bent angle is now a bit narrowly distributed in 135° × 15°. In the present study another distortion at Trp-19 and IIe-20 becomes conspicuous. The average root-mean-square displacement of atoms is now much smaller and is 1.5 Å for all backbone atoms. In the present paper side chain conformations are also analyzed.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090202
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  • 30
    Electronic Resource
    Electronic Resource
    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090301
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    A metal-mediated hydride shift mechanism for xylose isomerase based on the 1.6 Å Streptomycs rubiginosus structure with xylitol and D-xylose (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 153-173 
    Details
    ISSN: 0887-3585
    Keywords: crystallographic ; manganese ; ring opening ; X-ray ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The crystal structure of recombinant Streptomyces rubiginous D-xylose isomerase (D-xylose keto-isomerase, EC 5.3.1.5) solved by the multiple isomorphous replacement technique has been refined to R = 0.16 at 1.64 Å resolution. As observed in an earlier study at 4.0 Å (Carrell et al., J. Biol. Chem. 259: 3230-3236, 1984), xylose isomerase is a tetramer composed of four identical subunits. The monomer consists of an eight-stranded parallel β-barrel surrounded by eight helices with an extended C-terminal tail that provides extensive contacts with a neighboring monomer. The active site pocket is defined by an opening in the barrel whose entrance is lined with hydrophobic residues while the bottom of the pocket consists mainly of glutamate, aspartate, and histidine residues coordinated to two manganese ions.The structures of the enzyme in the presence of MnCl2, the inhibitor xylitol, and the substrate D-xylose in the presence and absence of MnCl2 have also been refined to R = 0.14 at 1.60 Å, R = 0.15 at 1.71 Å, R = 0.15 at 1.60 Å, and R = 0.14 at 1.60 Å, respectively. Both the ring oxygen of the cyclic α-D-xylose and its C1 hydroxyl are within hydrogen bonding distance of NE2 of His-54 in the structure crystallized in the presence of D-xylose. Both the inhibitor, xylitol, and the extended form of the substrate, D-xylose, bind such that the C2 and C4 OH groups interact with one of the two divalent cations found in the active site and the C1 OH with the other cation. The remainder of the OH groups hydrogen bond with neighboring amino acid side chains.A detailed mechanism for D-xylose isomerase is proposed. Upon binding of cyclic α-D-xylose to xylose isomerase, His-54 acts as the catalytic base in a ring opening reaction. The ring opening step is followed by binding of D-xylose, in volving two divalent cations, in an extended conformation. The isomerization of D-xylose to D-xylulose involves a metal-mediated 1,2-hydride shift. The final step in the mechanism is a ring closure to produce α-D-xylulose. The ring closing is the reverse of the ring opening step.This mechanism accounts for the majority of xylose iomerase's biochemical properties, in cluding (1) the lack of solvent exchange between the 2-position of D-xylose and the 1-pro-R position of D-xylulose, (2) the chemical modification of histidine and lysine, (3) the pH vs. activity profile, and (4) the requirement for two divalent cations in the mechanism.
    Additional Material: 13 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090302
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  • 32
    Electronic Resource
    Electronic Resource
    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090401
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  • 33
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    Thiol protease-like active site found in the enzyme dienelactone hydrolase: Localization using biochemical, genetic, and structural tools (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 267-279 
    Details
    ISSN: 0887-3585
    Keywords: DLH ; serine/cysteine protease ; X-ray crystal structure ; catalytic triad ; mutagenesis ; refinement ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The active site of dienelactone hydrolase (DLH), a microbial enzyme of the β-ketoadipate pathway, has been conclusively located using a combination of crystallographic, biochemical, and genetic techniques. DLH hydrolyzes a dienelactone to maleylacetate and has esterase activity on p-nitrophenyl acetate and trans-cinnamoyl imidazole. The identification of Cys-123 as containing the essential thiol confirms the localization of the active site as suggested by the crystal structure of DLH, and disproves an earlier hypothesis regarding its location. Two mutant proteins have been engineered in which Cys-123 has been converted to a serine (C123S DLH) and an alanine (C123A DLH), respectively. C123S DLH (Km = 9900±2300 μM; Vmax = 4.4±0.8 μmol/min-mg) displays burst kinetics with p-nitrophenyl acetate and is 10% as active as DLH (Km = 170±7 μM; Vmax = 21.1±0.4 μmol/min-mg). C123A DLH is inactive. The structures of DLH, C123S DLH, and C123A DLH have been refined at 1.8, 2.2, and 2.0 Å, respectively. Comparison of the structures of these proteins demonstrates that the only differences between them are centered at residue 123. The structures of the active sites of DLH, papain, and subtilisin are similar and are suggestive of the three enzymes having evolved convergently to similar active sites with similar enzymic mechanisms.
    Additional Material: 8 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090405
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  • 34
    Electronic Resource
    Electronic Resource
    Energetic approach to the folding of α/β barrels (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 280-295 
    Details
    ISSN: 0887-3585
    Keywords: staggering hydrogen bonds ; tilt ; twist ; βαβ crossover connection ; random generation of initial structures ; energy minimization ; associated loop energy ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The folding of a polypeptide into a parallel (α/β)8 barrel (which is also called a circularly permuted β8α8 barrel) has been investigated in terms of energy minimization. According to the arrangement of hydrogen bonds between two neighboring β-strands of the central barrel therein, such an α/β barrel structure can be folded into six different types: (1) left-tilted, left-handed crossover; (2) left-tilted, right-handed crossover; (3) nontilted, left-handed crossover; (4) nontilted, right-handed crossover; (5) right-tilted, left-handed crossover; and (6) right-tilted, right-handed crossover. Here “tilt” refers to the orientational relation of the β-strands to the axis of the central β-barrel, and “crossover” to the βαβ folding connection feature of the parallel β-barrel. It has been found that the right-tilted, right-handed crossover α/β barrel possesses much lower energy than the other five types of α/β barrels, elucidating why the observed α/β barrels in proteins always assume the form of right tilt and right-handed crossover connection. As observed, the β-strands in the energy-minimized right-tilted, right-handed crossover (α/β)8-barrel are of strong right-handed twist. The value of root-mean-square fits also indicates that the central barrel contained in the lowest energy (α/β)8 structure thus found coincides very well with the observed 8-stranded parallel β-barrel in triose phosphate isomerase (TIM). Furthermore, an energetic analysis has been made demonstrating why the right-tilt, right-handed crossover barrel is the most stable structure. Our calculations and analysis support the principle that it is possible to account for the main features of frequently occurring folding patterns in proteins by means of conformational energy calculations even for very complicated structures such as (α/β)8 barrels.
    Additional Material: 14 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090406
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  • 35
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    The crystal structure of staphylococcal nuclease refined at 1.7 Å resolution (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 92-105 
    Details
    ISSN: 0887-3585
    Keywords: protein structure ; ligand binding ; crystallographic refinement ; phosphodiesterase ; calcium ligands ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The crystal structure of staphylococcal nuclease has been determined to 1.7 Å resolution with a final R-factor of 16.2% using stereochemically restrained Hendrickson-Konnert least-squares refinement. The structure reveals a number of conformational changes relative to the structure of the ternary complex of staphylococcal nuclease1,2 bound with deoxythymidine-3′,5′-diphosphate and Ca2+. Tyr-113 and Tyr-115, which pack against the nucleotide base in the nuclease complex, are rotated outward creating a more open binding pocket in the absence of nucleotide. The side chains of Ca2+ ligands Asp-21 and Asp-40 shift as does Glu-43, the proposed general base in the hydrolysis of the 5′-phosphodiester bond. The significance of some changes in the catalytic site is uncertain due to the intrusion of a symmetry related Lys-70 side chain which hydrogen bonds to both Asp-21 and Glu-43. The position of a flexible loop centered around residue 50 is altered, most likely due to conformational changes propagated from the Ca2+ site. The side chains of Arg-35, Lys-84, Tyr-85, and Arg-87, which hydrogen bond to the 3′- and 5′-phosphates of the nucleotide in the nuclease complex, are unchanged in conformation, with packing interactions with adjacent protein side chains sufficient to fix the geometry in the absence of ligand. The nuclease structure presented here, in combination with the stereochemically restrained refinement of the nuclease complex structure2 at 1.65 Å, provides a wealth of structural information for the increasing number of studies using staphylococal nuclease as a model system of protein structure and function.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100203
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  • 36
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    Modelling the three-dimensional structure and electrostatic potential field of the two Cu,Zn superoxide dismutase variants from xenopus laevis (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 149-155 
    Details
    ISSN: 0887-3585
    Keywords: Cu,Zn superoxide dismutase ; model building ; protein structure-function ; Poisson-Boltzmann ; electrostatic potentials ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The crystallographic structure of bovine superoxide dismutase has been used as a template for the graphic reconstruction of the three-dimensional structures of the two Xenopus laevis variants (Schinina', M. E. et al. Arch. Biochem. Biophys. 272:507-515, 1989). In these models the structure-essential residues maintain their position and their structural role, and the interactions between the subunits and the close packing within the β-barrel are maintained with conservative substitutions and even increased with “aromatic pairs.” Because of the same topological motif and surface location of charges, arising from the model building of the two variants with respect to the bovine enzyme, we have calculated the electrostatic potential fields around the models of the two Xenopus laevis variants by numerically solving the Poisson-Boltzmann equation. We show that conservation of a specific space-relationship of charges maintains the potential field pattern already observed in the bovine enzyme, where a negative potential field surrounds the protein surface and specific positive regions wrap up the copper center active site. This electrostatic potential field distribution supports the idea that electrostatic interactions control, like in the bovine enzyme, the mechanism of enzyme-substrate recognition in the Xenopus laevis Cu,Zn superoxide dismutases, suggesting that coordinated mutation of charged residues has occurred in the evolution of this enzyme.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100208
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    Electronic Resource
    The future at proteins (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. i 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100302
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    On the multiple-minima problem in the conformational analysis of polypeptides. V. Application of the self-consistent electrostatic field and the electrostatically driven monte carlo methods to bovine pancreatic trypsin inhibitor (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 188-198 
    Details
    ISSN: 0887-3585
    Keywords: empirical potentials ; energy calculations ; protein structure prediction ; protein folding ; minimization ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: In connection with the accompanying paper to test various models for the hydration of polypeptides, we have explored a limited portion of the conformational energy hyperspace of the small protein bovine pancreatic trypsin inhibitor (BPTI) with the aid of two search methods developed in this laboratory. A series of low-energy conformations was obtained as a result of this study. These conformations constitute a set of local minima in the conformational energy space of the molecule as described by the ECEPP/2 (Empirical Conformational Energy Program for Peptides) potential energy function, without the inclusion of hydration. Five different initial conformations were used in this exploration: the first corresponds to an energy-refined structure based on the crystallographic coordinates (4PTI) provided by Deisenhofer and Steigemann25 and reported previously by Meirovitch and Scheraga.3 The remaining four initial conformations were obtained by using a Variable-Target-Function procedure, applied to the experimental Cartesian coordinates (5PTI) reported by Wlodawer et al.26The self-consistent electrostatic field (SCEF) and the electrostatically driven Monte Carlo (EDMC) methods were used to search the conformational space. The SCEF and EDMC methodologies assume that a polypeptide or protein molecule is driven toward the native structure mainly by the action of the electrostatic interactions. Application of these methodologies led to a set of conformations (up to 50 kcal/mol lower than the starting ones) with ECEPP/2 energies lower than any of those that we had previously found. Application of both methods to the initial conformation generated from 4PTI led to a series of low-energy conformations exhibiting similar rms deviations with respect to the experimental data (4PTI) as did the starting conformation. However, statistical analysis of the runs that had started from the conformations generated by using the variable-target-function procedure (and applying the EDMC method) indicated that the rms deviations of the atomic positions of the new low-energy conformations tended to increase as the energy improved, when compared with the X-ray data from which the starting conformations had been generated. The structures with the lowest energies also had radii of gyration smaller than the experimentally observed one. These results indicated a need to include hydration in the potential function, and provided the conformations used in the accompanying paper to test various hydration models.
    Additional Material: 6 Tab.
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    URL: http://dx.doi.org/10.1002/prot.340100304
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    Side chain-backbone hydrogen bonding contributes to helix stability in peptides derived from an α-helical region of carboxypeptidase A (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 130-139 
    Details
    ISSN: 0887-3585
    Keywords: α-helix ; side chain-backbone hydrogen bonding ; helix dipole ; circular dichroism ; carboxypeptidase A ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Recently, Presta and Rose proposed1 that a necessary condition for helix formation is the presence of residues at the N-and C-termini (called NTBs and CTBs) whose side chains can form hydrogen bonds with the initial four amides and the last four carbonyls of the helix, which otherwise lack intrahelical hydrogen bonding partners. We have tested this hypothesis by conformational analysis by circular dichroism (CD) of a synthetic peptide corresponding to a region (171-188) of the protein carboxypeptidase A; in the protein, residues 174 to 186 are helical and are flanked by NTBs and CTBs. Since helix formation in this peptide may also be stabilized by electrostatic interactions, we have compared the helical content of the native peptide with that of several modified peptides designed to enable dissection of different contributions to helix stability. As expected, helix dipole interactions appear to contribute substantially, but we conclude that hydrogen bonding interactions as proposed by Presta and Rose also stabilize helix formation. To assist in comparison of different peptides, we have introduced two concentration-independent CD parameters which are sensitive probes of helix formation.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100206
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    Free energy calculations on binding and catalysis by α-lytic protease: The role of substrate size in the P1 pocket (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 140-148 
    Details
    ISSN: 0887-3585
    Keywords: α-lytic protease ; free energy perturbation ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We present free energy calculations using molecular dynamics on different substrates of α-lytic protease in the gas phase, in solution, while forming a noncovalent Michaelis complex with the enzyme, and in a tetrahedral structure representing a transition state/intermediate for acylation by the enzyme. Various P1 substrates were studied, with P1 = Gly, Ala, Val, and Leu. In qualitative agreement with experiment, the enzyme was calculated to bind and catalyze most effectively substrates with P1 = Ala over those with P1 = Gly, Val or Leu. Also, the calculated relative solvation free energies of Gly → Ala and Ala → Val were in qualitative agreement with experimental values in corresponding model systems. However, the level of quantitative agreement with experiment achieved in our earlier study of relative binding and catalysis of native subtilisin and an Asn-155 → Ala mutant was not achieved. We surmise that this is due to the greater difficulty in quantitatively simulating effects that are predominantly van der Waals and hydrophobic compared to those that are hydrogen bonding/electrostatic.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100207
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    Modeling conformational change in macromolecules as an elastic deformation (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 162-170 
    Details
    ISSN: 0887-3585
    Keywords: conformation difference ; strain ; elasticity ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Macromolecules are elastic bodies. Atomic strucutres are available for nucleic acids and proteins in two or more different conformations. It is a common practice to compare two structures by finding the best rigid body superposition of the molecules. This ignores possible deformations. There is useful information in the deviations from the rigid body superposition. If the deviations are considered to be elastic deformations of a common structure than it is possible to extract this information. Results are shown for comparisons of deoxyhemoglobin versus carbonmonoxyhemoglobin and for two different conformations of catabolite gene activator protein.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100210
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    Empirical solvation models can be used to differentiate native from near-native conformations of bovine pancreatic trypsin inhibitor (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 199-218 
    Details
    ISSN: 0887-3585
    Keywords: empirical potentials ; energy calculations ; surface area ; protein stability ; protein folding ; protein structure prediction ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Several hydration models for peptides and proteins based on solvent accessible surface area have been proposed previously. We have evaluated some of these models as well as four new ones in the context of near-native conformations of a protein. In addition, we propose an empirical site-site distance-dependent correction that can be used in conjuction with any of these models.The set of near-native structures consisted of 39 conformations of bovine pancreatic trypsin inhibitor (BPTI) each of which was a local minimum of an empirical energy function (ECEPP) in the absence of solvent. Root-mean-square (rms) deviations from the crystallographically determined structure were in the following ranges: 1.06-1.94 Å for all heavy atoms, 0.77-1.36 Å for all backbone heavy atoms, 0.68-1.33 Å for all α-carbon atoms, and 1.41-2.72 Å for all side-chain heavy atoms.We have found that there is considerable variation among the solvent models when evaluated in terms of concordance between the solvation free energy and the rms deviations from the crystallographically determined conformation. The solvation model for which the best concordance (0.939) with the rms deviations of the Cα atoms was found was derived from NMR coupling constants of peptides in water combined with an exponential site-site distance dependence of the potential of mean force.Our results indicate that solvation free energy parameters derived from nonpeptide free energies of hydration may not be transferrable to peptides. Parameters derived from peptide and protein data may be more applicable to conformational analysis of proteins. A general approach to derive parameters for free energy of hydration from ensemble-averaged properties of peptides in solution is described.
    Additional Material: 8 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100305
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    Experimental and theoretical studies of the three-dimensional structure of human interleukin-4 (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 111-119 
    Details
    ISSN: 0887-3585
    Keywords: interleukin-4 ; circular dichroism spectroscopy ; site-directed mutagenesis ; protein structure modeling ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The structure of human interleukin 4 (IL-4) was predicted utilizing a series of experimental and theoretical techniques. Circular Dichroism (CD) spectroscopy indicated that IL-4 belonged to the all α-helix class of protein structures. Secondary structure prediction, site-directed mutagenesis, and CD spectroscopy suggested a predominantly α-helical structure, consistent with a four-helix bundle structural motif. A human/mouse IL-4 chimera was constructed to qualitatively evaluate alternative secondary structure predictions. The four predicted helices were assembled into tertiary structures using established algorithms. The mapping of three disulfide bridges in IL-4 provided additional constraints on possible tertiary structures. Using accessible surface contact area as a criterion, the most suitable structures were right handed all antiparallel four-helix bundles with two overhand loop connections. Successful loop closure and incorporation of the three disulfide constraints were possible while maintaining the expected shape, solvent accessibility, and steric interactions between loops and helices. Lastly, energy minimization was used to regularize the chain.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110204
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    Molecular dynamics simulations of the cytochrome c3-rubredoxin complex from Desulfovibrio vulgaris (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 142-152 
    Details
    ISSN: 0887-3585
    Keywords: AMBER ; electrostatics ; protein-protein interactions ; intermolecular bonding ; electron transfer ; redox proteins ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Molecular dynamics simulations have been carried out on the complex formed between the tetraheme cytochrome c3 and the iron protein rubredoxin from the sulfate-reducing bacterium Desulfovibrio vulgaris. These simulations were performed both with explicit solvent water molecules included, and without solvent molecules using a distance-dependent dielectric constant to approximate the screening effects of solvent. The results of both simulations are strikingly different, indicating that the representation of environmental effects is important in such simulations. For example, a striking adaptation of the two proteins seen in the nonsolvated simulation is not seen when explicit solvent water is included; in fact, the complex appears to become weaker in the solvated simulation. Nonetheless, the iron-iron distance decreases more significantly in the solvated simulation than in the nonsolvated simulation. It was found that in both cases molecular dynamics optimized the structures further than energy minimization alone.
    Additional Material: 11 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110207
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  • 45
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    Secondary structure-based profiles: Use of structure-conserving scoring tables in searching protein sequence databases for structural similarities (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 229-239 
    Details
    ISSN: 0887-3585
    Keywords: profile method ; sequence comparison ; secondary structure-based profile ; protein sequence data bases ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The profile method, for detecting distantly related proteins by sequence comparison, has been extended to incorporate secondary structure information from know X-ray structures. The sequence of a known structure is aligned to sequences of other members of a given folding class. From the known structure, the secondary structure (α-helix, β-strand or “other”) is assigned to each position of the aligned sequences. As in the standard profile method,1 a position-dependent scoring table, termed a profile, is calculated from the aligned sequences. However, rather than using the standard Dayhoff mutation table in calculating the profile, we use distinct amino acid mutation tables for residues in α-helices, β-strands or other secondary structures to calculate the profile. In addition, we also distinguish between internal and external residues. With this new secondary structure-based profile method, we created a profile for eight-stranded, antiparallel β barrels of the insecticyanin folding class. It is based on the sequences of retinol-binding protein, insecticyanin and β-lactoglobulin. Scanning the sequence database with this profile, it was possible to detect the sequence of avidin. The structure of streptavidin is known, and it appears to be distantly related to the antiparallel β barrels. Also detected is the sequence of complement component C8, which we therefore predict to be a member of this folding class.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100307
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    Electronic Resource
    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100401
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  • 47
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    Variation of folded polypeptide surface area with probe size (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 300-314 
    Details
    ISSN: 0887-3585
    Keywords: accessible area ; contact area ; molecular surface ; fractal dimension ; helices ; globins ; variable probe radius ; analytical surface models ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Three types of polypeptide surface area (contact, accessible, and molecular) have been studied as a function of the radius of a probe sphere used to map the surface. The surfaces are: (1) three α-helices, the H-helix of myoglobin, the E-helix of leghemoglobin, and an artificial polyalanine helix, each with 26 residues; (2) two globins, myoglobin and leghemoglobin, each with 153 residues: and (3) a two center model system for which the three types of surface area have been calculated analytically. The two globin helices have almost identical surface areas as a function of probe size as do the two globins. The polyalanine helix surface area is smaller but similar in shape to the globin helix areas. All three helix contact areas tend to the same limit as the probe size increases, and the globin contact areas behave similarly. Fractal dimensions were calculated for the helix and globin contact and molecular surfaces. All fractal dimensions showed strong dependence on probe size. The contact fractal dimension peaks at larger values for both the helices and globins. Most residues do not make contact with large probes (15 Å).
    Additional Material: 13 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100404
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    Electronic Resource
    Electronic Resource
    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110101
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    Structural and functional relations among thioredoxins of different species (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 13-28 
    Details
    ISSN: 0887-3585
    Keywords: thiol-dependent redox proteins ; redox-active disulfide ; sequence homology ; three-dimensional structure ; molecular modeling ; protein domains ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Three-dimensional models have been constructed of homologous thioredoxins and protein disulfide isomerases based on the high resolution x-ray crystallographic structure of the oxidized form of Escherichia coli thioredoxin. The thioredoxins, from archebacteria to humans, have 27-69% sequence identity to E. coli thioredoxin. The models indicate that all the proteins have similar three-dimensional structures despite the large variation in amino acid sequences. As expected, residues in the active site region of thioredoxins are highly conserved. These include Asp-26, Ala-29, Trp-31, Cys-32, Gly-33, Pro-34, Cys-35, Asp-61, Pro-76, and Gly-92. Similar residues occur in most protein disulfide isomerase sequences. Most of these residues form the surface around the active site that appears to facilitate interactions with other enzymes.Other structurally important residues are also conserved. A proline at position 40 causes a kink in the alpha-2 helix and thus provides the proper position of the active site residues at the amino end of this helix. Pro-76 is important in maintaining the native structure of the molecule. In addition, residues forming the internal contact surfaces between the secondary structural elements are generally unchanged such as Phe-12, Val-25, and Phe-27.
    Additional Material: 9 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110103
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    Gly-238-Ser substitution changes the substrate specificity of the SHV class A β-lactamases (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 45-51 
    Details
    ISSN: 0887-3585
    Keywords: third generation cephalosporins ; cefotaxime resistance ; enzyme structure-function ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The SHV-type β-lactamase SHV-2A is related to SHV-1 by a Gly-238-Ser replacement. Strains carrying SHV-2A are resistant to the third generation cephems cefotaxime and ceftizoxime, whereas those that carry SHV-1 are sensitive to these drugs. We present a kinetic analysis of a SHV-1 and SHV-2A enzymes, with the goal of gaining insight into the role of residue 238 in hydrolyzing cefotaxime and ceftizoxime. SHV-2A shows altered kinetic properties for a number of other cephems that also have heterocyclic side chains at the amino position of the 7-aminocephalosporanic acid nucleus (R1 side chain), including a significantly higher kcat/Km than does SHV-1 for cephaloridine, cephalothin, and cefotiam. Two cephems with straight chain R1 substitutions, cephalosporin C and cephacetrile, are not hydrolyzed more efficiently by SHV-2A. These results indicate that the Ser-238-Gly substitution increases the affinity toward cephems with a heterocyclic ring in the R1 side chain. In addition, the data for ampicillin and benzylpenicillin show that addition of a nitrogen to the second carbon of the R1 side chain of a penem results in a lower kcat/Km for SHV-2A relative to SHV-1. These data strongly suggest that the previously proposed hydrogen bond formation between Ser-238 and the second carbon nitrogen of cefotaxime is not an important factor in hydrolysis by SHV-2A. We propose that the Gly-238 to Ser-238 replacement in SHV-2A has altered the hydrophobic pocket so that it can better accommodate cephems with bulky R1 side chains.
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    URL: http://dx.doi.org/10.1002/prot.340110106
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    A model for human cardiac troponin C and for modulation of its Ca2+ affinity by drugs (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 79-94 
    Details
    ISSN: 0887-3585
    Keywords: TnC ; calmodulin ; trifluoperazine ; bepridil ; pimobendan ; calcium sensitivity ; inotropic ; muscle contraction ; energy minimization ; binding energy ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Calcium sensitizers are drugs which increase force development in striated muscle by sensitizing myofilaments to Ca2+. This can happen by increasing Ca2+ affinity of the regulatory domain of Ca2+ binding protein troponin C. High resolution crystal structures of two calcium binding proteins, calmodulin (Babu et al.: J. Mol. Biol. 203:191-204, 1988) and skeletal troponin C (Satyshur et al.: J. Biol. Chem. 263:1628-1647, 1988; Herzber et al.: J. Mol. Biol. 203:761-779, 1988), have recently been published. This makes it possible to model in detail the calcium-sensitizing action of drugs on troponin C.In this study a model of human cardiac troponin C in three-calcium state has been constructed. When calcium is bound to calcium site II of cardiac troponin C an open conformation of the protein results, which has a hydrophobic pocket surrounded by a few polar side chains. Complexation of three drugs, trifluoperazine, bepridil, and pimobendan, to the hydrophobic pocket is studied using energy minimization techniques. Two different binding modes are found, which differ in the location of a strong electrostatic interaction. In analogy with the crystal structure of skeletal troponin C it is hypothezed that in cardiac troponin C an interaction occurs between Gln-50 and Asp-88, which has a long-range effect on calcium binding. The binding modes of drugs, where a strong interaction with Asp-88 exists, can effectively prevent the interaction between Asp-88 and Gln-50 in the protein, and are proposed to be responsible for the calcium-sensitizing properties of the studied drugs.
    Additional Material: 10 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110202
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    Crystallization and preliminary analysis of enzyme-substrate complexes of pyruvate kinase from rabbit muscle (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 153-157 
    Details
    ISSN: 0887-3585
    Keywords: pyruvate kinase ; crystals ; electron paramagnetic resonance ; oxalate ; pyruvate ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Pyruvate kinase from rabbit muscle has been crystallized in a form suitable for high resolution X-ray analysis. Complexes of the enzyme with Mn2+ and either pyruvate or oxalate crystallize from solutions of polyethyleneglycol 8000 at pH 6.0. Crystals obtained from solutions of the complexes with pyruvate or oxalate appear isomorphous and belong to the triclinic space group P1. The crystals have unit cell dimensions a = 83.3(4) Å, b = 109.4(6) Å, c = 145.7(7) Å, α = 94.9°, β = 93.6°, γ = 112.2°. These crystals diffract to better than 2.4 Å resolution and are stable in the X-ray beam for at least 20 hr. Electron paramagnetic resonance measurements on a single crystal show that Mn2+ is bound to the crystalline protein.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110208
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    Thiol proteases and aldehyde dehydrogenases: Evolution from a common thiolesterase precursor? (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 176-183 
    Details
    ISSN: 0887-3585
    Keywords: active site model ; thiolester mechanism ; multiple alignment ; three-dimensional correlations ; conservation of glycines ; conservation of functional cysteines ; conservation of salt bridges ; exon boundaries ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The C-terminal 222 residues of human liver aldehyde dehydrogenase can be aligned with the C-terminal 226 residues of a thiol protease from Dictyostelium discoideum to yield 47 residue identities, including matching active site cysteine residues. A multiple alignment with three more aldehyde dehydrogenases and three more thiol proteases yields three regions with clustered residue similarities. In the tertiary structure of papain, these three regions are in close proximity although widely separated in primary structure, and many conserved residues are located in the active site groove. The three-dimensional relationships, the common thiol ester mechanisms of the enzymes, the locations of exon boundaries in the dehydrogenase and protease genes, and the conservation of internal salt-bridging and disulfide-paired residues in papain, all appear compatible with the hypothesis of an ancestral relationship between thiol proteases and aldehyde dehydrogenases.
    Additional Material: 2 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110303
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    Weak correlation between predictive power of individual sequence patterns and overall prediction accuracy in proteins (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 69-78 
    Details
    ISSN: 0887-3585
    Keywords: structure database ; amino acid properties ; early folding intermediates ; stable peptide structures ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Patterns in amino acid properties (polar, hydrophobic, etc.) that characterize secondary structure motifs are derived from a database containing 75 protein structures, with the aim of circumventing the limitations due to data base size so as to increase structure prediction score. Many such sequence-structure associations with high intrinsic predictive power are found, which turn out to be correct 78% of the time when applied individually to proteins outside the learning set. Based on these associations, a prediction method is developed, which reaches the socre of 62% on the 3 states α-helix, β-strand, and loop, without using additional constraints. Though this score is quite good compared to that of other available prediction methods, it is much lower than could be expected from the high intrinsic predictive power of the associations used. The reasons underlying this surprising result, which indicate that prediction score and intrinsic predictive power are only weakly coupled, are discussed. It is also shown that the size of the present database still seriously limits prediction scores, even when property patterns are used, and that higher scores are expected in large databases. Clues are provided on the relative influence of neglecting spatial interactions on prediction efficiency, suggesting that, in sufficiently large databases, predicted secondary structures would correspond to those formed early in the folding process. This hypothesis is tested by confronting present predictions with available experimental data on early protein folding intermediates and on small peptides that adopt a relatively stable conformation in water. Although admittedly there are still too few such data, results suggest that the hypothesis might be well founded.
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    URL: http://dx.doi.org/10.1002/prot.340090108
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    The frequency of ion-pair substructures in proteins is quantitatively related to electrostatic potential: A statistical model for nonbonded interactions (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 108-119 
    Details
    ISSN: 0887-3585
    Keywords: protein structure ; statistical analysis ; ion pairs ; electrostatic potential ; maximum likelihood ; maximum entropy ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A statistical analysis of ion pairs in protein crystal structures shows that their abundance with respect to uncharged controls is accurately predicted by a Botlzmann-like function of electrostatic potential. It appears that the mechanisms of protein folding and/or evolution combine to produce a “thermal” distribution of local nonbonded interactions, as has been suggested by statistical-mechanical theories. Using this relationship, we develop a maximum likelihood methodology for estimation of apparent energetic parameters from the data base of known structures, and we derive electrostatic potential functions that lead to optimal agreement of observed and predicted ion-pair frequencies. These are similar to potentials of mean force derived from electrostatic theory, but departure from Coulombic behavior is less than has been suggested.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090205
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    Predicted three-dimensional structure of the protease inhibitor domain of the Alzheimer's disease β-amyloid precursor (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 1-11 
    Details
    ISSN: 0887-3585
    Keywords: protein modeling ; protein homology ; trypsin ; bovine pancreatic trypsin inhibitor ; protein electrostatics ; amyloid protease inhibitor domain ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Alzheimer's disease is characterized by the deposition of amyloid β-protein as plaques and tangles in the brains of its victims. The amyloid precursor can be expressed with or without the inclusion of a protease inhibitor domain, the potential role of which in amyloidogenesis has prompted the generation of a model of its three-dimensional structure based on the known structure of a related inhibitor. The model structure predicts that the mutated residues are almost entirely on the surface of the inhibitor domain, while conserved residues constitute the hydrophobic core. In addition, several pairs of structurally complementary, or concerted, mutations are seen. These structural features provide strong evidence for the validity of the modeled structure, and it is suggested that the presence of complementary mutations may be used as a criterion for evaluating protein structures built by homology, in addition to the (spatial) location of the mutations. The terminal residues delimiting the domain are among those furthest from the protease binding site and are in close proximity to one another, thus suggesting the ability of the domain to function as a structural cassette within the context of a larger protein. The electrostatic potentials of the inhibitor and of the related bovine pancreatic trypsin inhibitor reveal how two inhibitors with very different net charges can bind with approximately the same binding constant to trypsin and suggest a mutation of trypsin that might selectively enhance the binding of the amyloid inhibitor domain. The model provides a structural basis for understanding the functional roles of residues in the domain and for designing simpler molecules to test as pharmacologic agents for intervention in Alzheimer's disease.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090102
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    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340090201
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    Crystallization of yeast orotidine 5′-monophosphate decarboxylase complexed with 1-(5′-phospho-β-D-ribofuranosyl) barbituric acid (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 143-151 
    Details
    ISSN: 0887-3585
    Keywords: BMP ; ODCase ; OMP ; pyrimidine biosynthesis ; incomplete factorial ; crystal growth ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Using an incomplete factorial experimental design, we have identified conditions for crystallization of yeast orotidine 5′-monophosphate decarboxylase (ODCase) in an unliganded state and complexed separately to two inhibitors: 6-azauridine 5′-monophosphate (aza-UMP) and 1-(5′-phospho-β-D-ribofuranosyl) barbituric acid (BMP). Crystals of X-ray diffraction quality have been obtained of yeast ODCase complexed with BMP, a putative transition state analog inhibitor (Ki = 8.8 × 10-12 M). ODCase:BMP complex crystals with a hexagonal rod habit were grown from a solution initially containing 12 mg/ml ODCase (205 μM dimer) plus 450 μM BMP by microdialysis at 4°C against a mother liquor which consisted of 0.1 M Na-PIPES-acetate (pH 6.4), 37.5 μM BMP, 5 mM mercaptoethanol, 1% polyethylene glycol 400, and 2.3 M ammonium sulfate. Crystals were analyzed using precession photography and were assigned to trigonal space group R32 with unit cell dimensions a = b = 115 Å, c = 385 Å. The crystal density is 1.245 g/cm3 indicating the presence of two ODCase:BMP complex dimers (118 kDa each) per asymmetric unit with a packing density of 2.08 Å3/Da and 41% solvent content. The morphological habit of crystals of the ODCase:BMP complex changed when the initial ammonium sulfate concentration was increased in 0.05 M steps from 2.3 to 2.45 M. All of these crystals diffracted to at least 3.0 Å resolution over a period of several weeks at room temperature and are isomorphous.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090208
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    A workbench for multiple alignment construction and analysis (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 180-190 
    Details
    ISSN: 0887-3585
    Keywords: pattern recognition ; sequence alignment ; algorithms ; amino acid sequences ; molecular sequence data ; proteins ; software ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Multiple sequence alignment can be a useful technique for studying molecular evolution, as well as for analyzing relationships between structure or function and primary sequence. We have developed for this purpose an interactive program, MACAW (Multiple Alignment Construction and Analysis Workbench), that allows the user to construct multiple alignments by locating, analyzing, editing, and combining “blocks” of aligned sequence segments. MACAW incorporates several novel features. (1) Regions of local similarity are located by a new search algorithm that avoids many of the limitations of previous techniques. (2) The statistical significance of blocks of similarity is evaluted using a recently developed mathematical theory. (3) Candidate blocks may be evaluated for potential inclusion in a multiple alignment using a variety of visualization tools. (4) A user interface permits each blocks to be edited by moving its boundaries or by eliminating particular segments, and blocks may be linked to form a composite multiple alignment. No completely automatic program is likely to deal effectively with all the complexities of the multiple alignment problem; by combining a powerful similarity search algorithm with flexible editing, analysis and display tools, MACAW allows the alignment strategy to be tailored to the problem at hand.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090304
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    Topological mirror images in protein structure computation: An underestimated problem (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 22-32 
    Details
    ISSN: 0887-3585
    Keywords: distance geometry ; DISHAN ; DISGEO ; protein structure ; NMR ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: When calculating three-dimensional structures from NMR data, alternative solutions with very large RMS deviation can be obtained. Sometimes local or global inversions of the protein folding can be observed. We call these different solutions topological mirror images, as they keep the correct amino acid chirality. They are observed when the number of restraints is insufficient and represent different solutions from the same scalar information. Therefore they are common in small peptides where the NMR data are often limited and the secondary structure is not very well defined. They can also be observed in large molecules in regions of higher flexibility. In our experience the observation of topological mirror images is independent of the efficiency of sampling of the algorithm used. We present four examples of proteins with different size and folding. We also discuss ways to distinguish among the different solutions.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100104
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    The crystal structure of the “open” and the “closed” conformation of the flexible loop of trypanosomal triosephosphate isomerase (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 33-49 
    Details
    ISSN: 0887-3585
    Keywords: TIM ; molecular dynamics refinement ; loop movement ; conformational change ; crystal contacts ; sleeping sickness ; suramine ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Triosephosphate isomerase has an important loop near the active site which can exist in a “closed” and in an “open” conformation. Here we describe the structural properties of this “flexible” loop observed in two different structures of trypanosomal triosephosphate isomerase. Trypanosomal triosephosphate isomerase, crystallized in the presence of 2.4 M ammonium sulfate, packs as an asymmetric dimer of 54,000 Da in the crystallographic asymmetric unit. Due to different crystal contacts, peptide 167-180 (the flexible loop of subunit-1) is an open conformation, whereas in subunit-2, this peptide (residues 467-480) is in a closed conformation. In the closed conformation, a hydrogen bond exists between the tip of the loop and a well-defined sulfate ion which is bound to the active site of subunit-2. Such an active site sulfate is not present in subunit-1 due to crystal contacts. When the native (2.4 M ammonium sulfate) crystals are transferred to a sulfate-free mother liquor, the flexible loop of subunit-2 adopts the open conformation. From a closed starting model, this open conformation was discovered through molecular dynamics refinement without manual intervention, despite involving Cα shifts of up to 7 Å. The tip of the loop, residues 472, 473, 474, and 475, moves as a rigid body. Our analysis shows that in this crystal form the flexible loop of subunit-2 faces a solvent channel. Therefore the open and the closed conformations of this flexible loop are virtually unaffected by crystal contacts. The actual observed conformation depends only on the absence or presence of a suitable ligand in the active site.
    Additional Material: 16 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100105
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    The mutation β99 Asp-Tyr stabilizes Y - A new, composite quaternary state of human hemoglobin (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 81-91 
    Details
    ISSN: 0887-3585
    Keywords: mutant hemoglobin ; cooperativity ; protein structure ; conformational change ; quaternary structure ; allosteric proteins ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Carbonmonoxy hemoglobin Ypsilanti (β99 Asp-Tyr) exhibits a quaternary form distinctly different from any structures previously observed for human hemoglobins. The relative orientation of αβ dimers in the new quaternary form lies well outside the range of values observed for normal unliganded and liganded tetramers (Baldwin, J., Chothia, C., J. Mol. Biol. 129:175-220, 1979). Despite this large quaternary structural difference between carbonmonoxy hemoglobin Ypsilanti and the two canonical structures, the new quaternary structure's hydrogen bonding interactions in the “switch” region, and packing interactions in the “flexible joint” region, show noncovalent interactions characteristic of the α1β2 contacts of both unliganded and liganded normal hemoglobins. In contrast to both canonical structures, the β97 histidine residue in carbonmonoxy hemoglobin Ypsilanti is disengaged from quaternary packing interactions that are generally believed to enforce two-state behavior in ligand binding. These features of the new quaternary structure, denoted Y, may therefore be representative of quaternary states that occur transiently along pathways between the normal unliganded, T, and liganded, R, hemoglobin structures.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100202
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    Relaxation data in NMR structure determination: Model calculations for the lysozyme-Gd3+ complex (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 117-129 
    Details
    ISSN: 0887-3585
    Keywords: protein NMR ; distance restraints ; paramagnetic relaxation ; protein structure determination ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The effect of including paramagnetic relaxation data as additional restraints in the determination of protein tertiary structures from NMR data has been explored by a systematic series of model calculations. The system used for testing the method was the 2.0 Å resolution tetragonal crystal structure of hen egg white lysozyme (129 amino acid residues) and structures were generated using a version of the hybrid “distance geometry-dynamic simulated annealing” procedure. A limited set of 769 NOEs was used as restraints in all the calculations; the strengths of these were categorized into three classes on the basis of distances observed in the crystal structure. The values of 50 φ angles were also restrained on the basis of amide-alpha coupling constants calculated from the X-ray structure. Five sets of 12 structures were determined using differing sets of paramagnetic relaxation data as restraints additional to those involving the NOE and coupling constant data. The paramagnetic relaxation data were modeled on the basis of the distances of defined protons from the crystallographic binding site of Gd3+ in lysozyme. Analysis of the results showed that the relaxation data significantly improved the correspondence between the set of generated structures and the crystal structure, and that the more well defined the relaxation data, the more significant the improvement in the quality of the structures. The results suggest that the inclusion of paramagnetic relaxation restraints could be of significant value for the experimental determination of protein structures from NMR data.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100205
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    Structure of ricin B-chain at 2.5 Å resolution (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 260-269 
    Details
    ISSN: 0887-3585
    Keywords: ricin toxin ; B-chain ; galactose binding ; molecular evolution ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The heterodimeric plant toxin ricin has been refined to 2.5 Å resolution. The B-chain lectin (RTB) is described in detail. The protein has two major domains, each of which has a galactose binding site. RTB has no regular secondary structure but displays several Ω loops. Each RTB domain is made of three copies of a primitive 40 residue folding unit, which pack around a pseudo threefold axis. In each domain, galactose binds in a shallow cleft formed by a three residue peptide kink on the bottom and an aromatic ring on the top. At the back of the cleft, an aspartate forms hydrogen bonds to the C3 and C4 hydroxyls of galactose, whereas a glutamine bonds to the C4 alcohol, helping to define specific epimer binding. In addition to analyzing the sugar binding mechanism, the assembly of subdomain units around the pseudo threefold axis of each domain is described. The subdomains contribute conserved Trp, Leu, and Ile residues to a compact central hydrophobic core. This tight threefold binding probably drives the peptide folding and stabilizes the protein structure.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100310
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    Active site conformation in myoglobin as determined by X-ray absorption spectroscopy (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 279-286 
    Details
    ISSN: 0887-3585
    Keywords: myoglobin ; structure of the active site ; XAFS Debye-Waller factor ; Einstein model ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: X-ray absorption fine structure experiments were performed to study structural and dynamic aspects of the active site of various forms of myoglobin. The structures determined for deoxyMb, MbCO, and MbO2 are consistent with the structure established by X-ray absorption fine structure experiment and X-ray crystallography. The first shell of ferrous MbNO determined contains 5 nitrogens located at 2.02 Å and a short NO bond length of 1.76 Å. This study focuses on the change of the XAFS Debye-Waller factor with temperature, which is a measure of thermal and static disorder. It was found that the changes of Debye-Waller factor with temperature for the Mb proteins, except deoxyMb, are consistent with a simple Einstein model, in which a single frequency was assumed for the bond stretching modes. In contrast, the temperature dependence of deoxyMb cannot be fitted to the Einstein model and a large disorder was found at low temperatures, which indicates the existence of conformational substates of the active site.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100402
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    Physical reasons for secondary structure stability: α-Helices in short peptides (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 287-299 
    Details
    ISSN: 0887-3585
    Keywords: polypeptides ; α-helix ; secondary structure ; protein folding ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: It was recently found that some short peptides (including C- and S-peptide fragments of RNase A) can have considerable helicity in solution, 1-12 which was considered to be surprising. Does the observed helicity require a new explanation, or is it consistent with previous understanding? In this work we show that this helicity is consistent with the physical theory of secondary structure12-19 based on an extension of the conventional Zimm-Bragg model.20 Without any special modifications, this theory explains reasonably well almost all the experimentally observed dependencies of helicity on pH, temperature, and amino acid replacements. We conclude that the observed “general level” of helicity of C- and S-peptides (5-30% at room temperature and 10-50% near 0°C) is “normal” for short peptides consisting mainly of helix-forming and helix-indifferent residues. The helicity is modified by a multitude of weak specific side chain interactions, many of which are taken into account by the present theory;13-19 some discrepancies between the theory and experiment can be explained by weak side-chain-side chain interactions that were neglected. A reasonable coincidence of the theory with experiment suggests that it had been used to investigate the role of local interactions in the formation of α-helical “embryos” in unfolded protein chains.
    Additional Material: 9 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100403
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    Comparative analysis of the sequences and structures of HIV-1 and HIV-2 proteases (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 325-339 
    Details
    ISSN: 0887-3585
    Keywords: retroviral proteases ; aspartic proteases ; HIV ; protease inhibitors ; sequence analysis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The different isolates available for HIV-1 and HIV-2 were compared for the region of the protease (PR) sequence, and the variations in amino acids were analyzed with respect to the crystal structure of HIV-1 PR with inhibitor. Based on the extensive homology (39 identical out of 99 residues), models were built of the HIV-2 PR complexed with two different aspartic protease inhibitors, acetylpepstatin and a renin inhibitor, H-261. Comparison of the HIV-1 PR crystal structure and the HIV-2 PR model structure and the analysis of the changes found in different isolates showed that correlated substitutions occur in the hydrophobic interior of the molecule and at surface residues involved in ionic or hydrogen bond interactions. The substrate binding residues of HIV-1 and HIV-2 PRs show conservative substitutions of four residues. The difference in affinity of HIV-1 and HIV-2 PRs for the two inhibitors appears to be due in part to the change of Val 32 in HIV-1 PR to Ile in HIV-2 PR.
    Additional Material: 14 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100406
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    Functionality maps of binding sites: A multiple copy simultaneous search method (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 29-34 
    Details
    ISSN: 0887-3585
    Keywords: drug-design ; ligand-binding ; hemagglutinin ; functional groups ; MCSS ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A new method is proposed for determining energetically favorable positions and orientations for functional groups on the surface of proteins with known three-dimensional structure. From 1,000 to 5,000 copies of a functional group are randomly placed in the site and subjected to simultaneous energy minimization and/or quenched molecular dynamics. The resulting functionality maps of a protein receptor site, which can take account of its flexibility, can be used for the analysis of protein ligand interactions and rational drug design. Application of the method to the sialic acid binding site of the influenza coat protein, hemagglutinin, yields functional group minima that correspond with those of the ligand in a cocrystal structure.
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    URL: http://dx.doi.org/10.1002/prot.340110104
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    Detection of common three-dimensional substructures in proteins (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 52-58 
    Details
    ISSN: 0887-3585
    Keywords: protein structure comparison ; superposition ; clustering ; folding units ; sequence alignment ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We present a fully automatic algorithm for three-dimensional alignment of protein structures and for the detection of common substructures and structural repeats. Given two proteins, the algorithm first identifies all pairs of structurally similar fragments and subsequently clusters into larger units pairs of fragments that are compatible in three dimensions. The detection of similar substructures is independent of insertion/deletion penalties and can be chosen to be independent of the topology of loop connections and to allow for reversal of chain direction. Using distance geometry filters and other approximations, the algorithm, implemented in the WHAT IF program, is so fast that structural comparison of a single protein with the entire database of known protein structures can be performed routinely on a workstation. The method reproduces known non-trivial superpositions such as plastocyanin on azurin. In addition, we report surprising structural similarity between ubiquitin and a (2Fe-2S) ferredoxin.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110107
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    Expert system for predicting protein localization sites in gram-negative bacteria (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 95-110 
    Details
    ISSN: 0887-3585
    Keywords: expert system ; prediction from amino acid sequences ; sorting of proteins ; gram-negative bacteria ; genome analysis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We have developed an expert system that makes use of various kinds of knowledge organized as “if-then” rules for predicting protein localization sites in Gram-negative bacteria, given the amino acid sequence information alone. We considered four localization sites: the cytoplasm, the inner (cytoplasmic) membrane, the periplasm, and the outer membrane. Most rules were derived from experimental observations. For example, the rule to recognize an inner membrane protein is the presence of either a hydrophobic stretch in the predicted mature protein or an uncleavable N-terminal signal sequence. Lipoproteins are first recognized by a consensus pattern and then assumed present at either the inner or outer membrane. These two possibilities are further discriminated by examining an acidic residue in the mature N-terminal portion. Furthermore, we found an empirical rule that periplasmic and outer membrane proteins were successfully discriminated by their different amino acid composition. Overall, our system could predict 83% of the localization sites of proteins in our database.
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    URL: http://dx.doi.org/10.1002/prot.340110203
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    Review of macimdad®: Molecular graphics presentation for the macintosh® (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 158-158 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110209
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    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110301
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    A 175-psec molecular dynamics simulation of camphor-bound cytochrome P-450cam (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 184-204 
    Details
    ISSN: 0887-3585
    Keywords: heme enzyme ; Pseudomonas putida ; conformational flexibility ; protein dynamics ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The structure and internal motions of cytochrome P-450cam, a monooxygenase heme enzyme with 414 amino acid residues, with camphor bound at the active site have been evaluated on the basis of a 175-psec molecular dynamics simulation carried out at 300 K. All hydrogen atoms were explicitly modeled, and 204 crystallographic waters were included in the simulation. Based on an analysis of the time course of the trajectory versus potential energy, root mean square deviation, radius of gyration, and hydrogen bonding, the simulation was judged to be stable and representative of the average experimental structure. The averaged structural properties of the enzyme were evaluated from the final 135 psec of the simulation. The average atomic displacement from the X-ray structure was 1.39 Å for all heavy atoms and 1.17 Å for just C-α atoms. The average root-mean-square (rms) fluctuations of all heavy atoms and backbone atoms were 0.42 and 0.37 Å, respectively. The computed rms fluctuations were in reasonable agreement with the experimentally determined temperature factors. All 13 segments of α-helix and 5 segments of β-sheet were well preserved with the exception of the N-terminal half of halix F which alternated between an α-helix and a 310-helix. In addition there were in general only small variations in the relative orientation of adjacent α-helices. The rms fluctuations of the backbone dihedral angles in the secondary structure elements were almost uniformly smaller, with the fluctuation in α-helices and β-sheets, 31 and 10% less, respectively, than those in nonsecondary structure regions. The reported crystal structure contains kinks in both helices C and I. In the simulation, both of these regions showed high mobility and large deviations from their starting positions. Since the kink in the I helix is at the oxygen binding site, these motions may have mechanistic implications.
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    URL: http://dx.doi.org/10.1002/prot.340110304
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    Crystallization and preliminary X-ray investigation of a recombinant form of rat catechol O-methyltransferase (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 233-236 
    Details
    ISSN: 0887-3585
    Keywords: protein crystals ; X-ray crystallography ; catechol O-methyltransferase ; protein structure ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Rat catechol O-methyltransferase cDNA was introduced into an E. coli expression vector pKEX14, which utilizes the inducible T7 promoter. Active and soluble recombinant catechol O-methyltransferase was produced in bacteria and purified to electrophoretic homogeneity by chromatographic procedures. The purified enzyme has been crystallized by the method of vapor diffusion using polyethylene glycol as precipitant. The space group is P3121 or P3221 with a = b = 51.3 Å and c = 168.5 Å and one molecule in the asymmetric unit. The crystals diffract beyond 3.2 Å and are suitable for three-dimensional X-ray structure determination.
    Additional Material: 3 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110309
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    FASTRUN: A special purpose, hardwired computer for molecular simulation (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 242-253 
    Details
    ISSN: 0887-3585
    Keywords: FASTRUN ; special purpose processors ; computer hardware ; molecular mechanics ; supercomputing ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We describe the design, construction, and performance of a special purpose, hardwired accelerator for molecular mechanical calculations called FASTRUN. The processor was designed at Columbia University in 1984, constructed in the Instrumentation Division of Brookhaven National Laboratory, and delivered to Columbia in final form in 1989. It was rendered functional for molecular mechanics in early 1990. Together with its host Star array processor, FASTRUN has a measured performance for molecular dynamics simulations which compares favorably with present day supercomputers. The hardware replication cost of FASTRUN is on the order of $100,000.00
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110403
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    Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 281-296 
    Details
    ISSN: 0887-3585
    Keywords: hydrophobicity ; surface tension ; protein folding ; protein association ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We demonstrate in this work that the surface tension, water-organic solvent, transfer-free energies and the thermodynamics of melting of linear alkanes provide fundamental insights into the nonpolar driving forces for protein folding and protein binding reactions. We first develop a model for the curvature dependence of the hydrophobic effect and find that the macroscopic concept of interfacial free energy is applicable at the molecular level. Application of a well-known relationship involving surface tension and adhesion energies reveals that dispersion forces play little or no net role in hydrophobic interactions; rather, the standard model of disruption of water structure (entropically driven at 25°C) is correct. The hydrophobic interaction is found, in agreement with the classical picture, to provide a major driving force for protein folding. Analysis of the melting behavior of hydrocarbons reveals that close packing of the protein interior makes only a small free energy contribution to folding because the enthalpic gain resulting from increased dispersion interactions (relative to the liquid) is countered by the freezing of side chain motion. The identical effect should occur in association reactions, which may provide an enormous simplification in the evaluation of binding energies. Protein binding reactions, even between nearly planar or concave/convex interfaces, are found to have effective hydrophobicities considerably smaller than the prediction based on macroscopic surface tension. This is due to the formation of a concave collar region that usually accompanies complex formation. This effect may preclude the formation of complexes between convex surfaces.
    Additional Material: 8 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340110407
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    1.59 Å structure of trypsin at 120 K: Comparison of low temperature and room temperature structures (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 171-187 
    Details
    ISSN: 0887-3585
    Keywords: cryocrystallography ; temperature factor ; serine protease structure ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The structure of a rat trypsin mutant [S195C] at a temperature of 120 K has been refined to a crystallographic R factor of 17.4% between 12.0 and 1.59 Å and is compared with the structure of the D102N mutant at 295 K. A reduction in the unit cell dimensions in going from room temperature to low temperature is accompanied by a decrease in molecular surface area and radius of gyration. The overall structure remains similar to that at room temperature. The attainable resolution appears to be improved due to the decrease in the fall off of intensities with resolution [reduction of the temperature factor]. This decreases the uncertainty in the atomic positions and allows the localization of more protein atoms and solvent molecules in the low temperature map. The largest differences between the two models occur at residues with higher than average temperature factors. Several features can be localized in the solvent region of the 120 K map that are not seen in the 295 K map. These include several more water molecules as well as an interstitial sulfate ion and two interstitial benzamidine molecules.
    Additional Material: 14 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100303
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    The isolation, purification, and preliminary crystallographic characterization of udp-galactose-4-epimerase from Escherichia coli (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 135-142 
    Details
    ISSN: 0887-3585
    Keywords: X-ray crystallography ; galactose metabolism ; nucleotide binding ; nonstereospecific hydride transfer ; protein structure ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Uridine diphosphogalactose-4-epimerase from E. coli has been crystallized in a form suitable for a high-resolution X-ray crystallographic structural analysis. The enzyme complexed with a substrate analogue, uridine diphosphobenzene (UDP-benzene), crystallizes readily using polyethylene glycol 8000 as the precipitant. The crystals belong to the orthorhombic space group P212121 with unit cell dimensions, a = 76.3 Å, b = 83.1 Å, and c = 132.1 Å. Based on still setting photographs, the crystals diffract to a nominal resolution of 2.3 Å and are stable in the X-ray beam. The enzyme used in these experiments was produced by a new expression system and a modified purification scheme.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090207
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    The three-dimensional structure of glutathione reductase from Escherichia coli at 3.0 Å resolution (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 174-179 
    Details
    ISSN: 0887-3585
    Keywords: glutathione reductase ; X-ray analysis ; molecular replacement ; sitedirected mutagenesis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The structure of glutathione reductase from Escherichia coli has been solved at 3 Å resolution using multiple isomorphous replacement, solvent flattening, and molecular replacement on the basis of the homologous (53% identical residues) and structurally well-established human enzyme. The structures of both enzyme species agree with each other in a global way; there is no domain rearrangement. In detail, clear structural differences can be observed. The structure analysis of the E. coli enzyme was tackled in order to understand sitedirected mutants, the most spectacular of which changed the cofactor specificity of this enzyme from NADP to NAD (Scrutton et al., 1990, Nature 343:38-43).
    Additional Material: 2 Ill.
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    Comparative modeling of mammalian aspartate transcarbamylase (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 191-206 
    Details
    ISSN: 0887-3585
    Keywords: CAD ; E. coli ATCase ; energy minimization ; multifunctional proteins ; protein domains ; sequence homology ; evaluation of protein models ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Mammalian aspartate transcarbamylase (ATCase) is part of a 243 kDa multidomain polypeptide, called CAD, that catalyzes the first three steps in de novo pyrimidine biosynthesis. The structural organization of the mammalian enzyme is very different from E. coli ATCase, a dodecameric, monofunctional molecule comprised of six copies of separate catalytic and regulatory chains. Nevertheless, sequence similarities and other properties suggested that the mammalian ATCase domain and the E. coli ATCase catalytic chain have the same tertiary fold. A model of mammalian ATCase was built using the X-ray coordinates of the E. coli catalytic chain as a tertiary template. Five small insertions and deletions could be readily accommodated in the model structure. Following energy minimization the RMS difference in the α carbon positions of the mammalian and bacterial proteins was 0.93 Å. A comparison of the hydrophobic energies, surface accessibility index, and the distribution of hydrophilic and hydrophobic residues of the CAD ATCase structure with correctly and incorrectly folded proteins and with several X-ray structures supported the validity of the model. The mammalian ATCase domain associates to form a compact globular trimer, a prerequisite for catalysis since the active site is comprised of residues from adjacent subunits. Interactions between the clearly defined aspartate and carbamyl phosphate subdomains of the monomer were largely preserved while there was appreciable remodeling of the trimeric interfaces. Several clusters of basic residues are located on the upper surface of the domain which account in part for the elevated isoelectric point (pI = 9.4) and may represent contact regions with other more acidic domains within the chimeric polypeptide. A long interdomain linker connects the monomer at its upper surface to the remainder of the polypeptide. The configuration of active site residues is virtually identical in the mammalian and bacterial enzymes. While the CAD ATCase domain can undergo the local conformational changes that accompany catalysis in the E. coli enzyme, the high activity, closed conformation is probably more stable in the mammalian enzyme.
    Additional Material: 12 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090305
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    Conformational perturbation of interleukin-2: A strategy for the design of cytokine analogs (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 207-216 
    Details
    ISSN: 0887-3585
    Keywords: interleukin-2 ; lymphokine structure ; α-helical proteins ; circular dichroism ; receptor signaling defect ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Interleukin-2 (IL-2) is a representative of a growing family of small proteins termed lymphokines which are responsible for mediating cell differentiation, growth and function in the immune system. Many of these proteins are being evaluated for their clinical potential. From the perspective of drug development, structure-function analysis of these molecules and their receptors require the use methodologies different than those traditionally employed for small peptides and other natural products. However, similar pharmacologic principles apply and an understanding of ligand-receptor interactions and the asssociated responses is required in order to efficiently pursue agonist and antagonist design.Although IL-2 is a protein of only 133 amino acid residues for which a low resolution X-ray structure does exist, the complexity of its receptor system has provided an added challenge to structure-function studies. Consequently, little is known concerning the receptor contact residues for this protein. We have attempted to utilize established principles of protein and peptide structure to manipulate the conformation of IL-2 in a manner which has provided analogs helpful for receptor interactions studies. These proteins have not only providing useful information on the nature of the IL-2 receptor but have also revealed potential strategies for the design of IL-2 agonists and antagonists.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090306
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    Hydrogen bonds involving sulfur atoms in proteins (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 99-107 
    Details
    ISSN: 0887-3585
    Keywords: protein structure ; hydrogen bonding ; interactions of side chains ; cysteine ; methionine ; half-cystine ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Intrachain hydrogen bonds are a hallmark of globular proteins. Traditionally, these involve oxygen and nitrogen atoms. The electronic structure of sulfur is compatible with hydrogen bond formation as well. We surveyed a set of 85 high-resolution protein structures in order to evaluate the prevalence and geometry of sulfur-containing hydrogen bonds. This information should be of interest to experimentalists and theoreticians intersted in protein structure and protein engineering.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090204
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    Role of conserved proline residues in stabilizing tryptophan synthase α subunit: Analysis by mutants with alanine or glycine (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 90-98 
    Details
    ISSN: 0887-3585
    Keywords: calorimetry ; unfolding of protein ; CD spectra ; denaturation by guanidine hydrochloride ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: To study the role of Pro residues in the conformation and conformational stability of a protein, nine mutant α subunits of tryptophan synthase from Escherichia coli, in which Ala or Gly was substituted for each of six Pro residues (positions 28, 57, 62, 96, 132, and 207) that are conserved in 10 microoganisms, were constructed by means of site-directed mutagenesis. The far-ultraviolet (UV) CD spectra of five mutant α subunits with Ala in place of Pro were identical to the spectrum of the wild-type protein, the exception being the mutant at position 207 (P207A). CD values in the far-UV region were less negative for P207A, indicating that the Pro residue at position 207 plays a role in maintaining the intact structure of the α subunit. The negative CD values of the Gly mutants examined (P28G, P96G, and P132G) were also decreased. Calorimetric measurements showed that the two mutants at position 28 (P28G and P28A) gave two peaks in the excess heat capacity curve, whereas the wild type and other Pro mutants had only a single peak. The stability of each mutant protein relative to that of the wild type was about the same for P57A, less for P62A and P132A, and markedly decreased for P96A and P207A, which are substituted at less mobile positions. The changes of denaturation entropy (ΔΔdS) at the denaturation temperature of the wild-type protein (54.1 °C at pH 9.0) were positive for P57A, P62A, and P132A, but negative for P96A, P207A, and P132G. The present results do not indicate that the differences in stability (ΔdG) among Pro substitutions are caused only by an entropic factor, as might be theoretically expected. The decreases in stability for P96A and P207 were due to the considerable decrease in denaturation enthalpy, although they were partly compensated for by the decrease in entropy. Our results also suggest that Pro-28 stabilizes the interaction between two domains of the α subunit.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090203
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    Single-stranded DNA binding proteins (SSBs) from prokaryotic transmissible plasmids (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 120-134 
    Details
    ISSN: 0887-3585
    Keywords: plasmid SSBs ; protein and DNA sequence ; single-stranded DNA binding proteins ; helix destabilizing proteins ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The DNA and protein sequences of single-stranded DNA binding proteins (SSBs) encoded by the plP71a, plP231a, and R64 conjugative plasmids have been determined and compared to Escherichia coli SSB and the SSB encoded by F-plasmid. Although the amino acid sequences of all of these proteins are highly conserved within the NH2-terminal two-thirds of the protein, they diverge in the COOH-terminal third region. A number of amino acid residues which have previously been implicated as being either directly or indirectly involved in DNA binding are conserved in all of these SSBs. These residues include Trp-40, Trp-54, Trp-88, His-55, and Phe-60. On the basis of these sequence comparisons and DNA binding studies, a role for Tyr-70 in DNA binding is suggested for the first time. Although the COOH-terminal third of these proteins diverges more than their NH2-terminal regions, the COOH-terminal five amino acid residues of all five of these proteins are identical. In addition, all of these proteins share the characteristic property of having a protease resistant, NH2-terminal core and an acidic COOH-terminal region. Despite the high degree of sequence homology among the plasmid SSB proteins, the F-plasmid SSB appears unique in that it was the only SSB tested that neither bound well to poly(dA) nor was able to stimulate DNA polymerase III holoenzyme elongation rates. Poly [d(A-T)] melting studies suggest that at least three of the plasmid encoded SSBs are better helix-destabilizing proteins than is the E. coli SSB protein.
    Additional Material: 10 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090206
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    Preliminary x-ray analysis of crystals of plasminogen activator inhibitor-1 (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 9 (1991), S. 225-227 
    Details
    ISSN: 0887-3585
    Keywords: protein crystals ; crystallography ; latency ; tissue plasminogen activator ; N-terminal ; methionine ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Crystals of bacterially expressed plasminogen activator inhibitor (PAI-1) suitable for X-ray diffraction analysis have been obtained from 8% (w/v) PEG 1500, pH 8.25. The space group is P1, and the lattice constants are a = 82.17 Å, b = 47.82 Å, c = 62.89 Å, α = 90.00°, β = 106.90°, γ = 106.84°. The diffraction limit is 2.3 Å, and the unit cell contains two molecules of PAI-1. The crystals contain latent PAI-1 which can be partly reactivated by exposure to denaturants.
    Additional Material: 1 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340090308
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    Comparison of the crystal structure of bacteriophage T4 lysozyme at low, medium, and high ionic strengths (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 10-21 
    Details
    ISSN: 0887-3585
    Keywords: electrostatics ; salt bridge ; thermal factor ; cysteine ; disulfide ; protein crystallography ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Crystals of bacteriophage T4 lysozyme used for structural studies are routinely grown from concentrated phosphate solutions. It has been found that crystals in the same space group can also be grown from solutions containing 0.05 M imidazole chloride, 0.4 M sodium choride, and 30% polyethylene glycol 3500. These crystals, in addition, can also be equilibrated with a similar mother liquor in which the sodium chloride concentration is reduced to 0.025 M. The availability of these three crystal variants has permitted the structure of T4 lysozyme to be compared at low, medium, and high ionic strength. At the same time the X-ray structure of phage T4 lysozyme crystallized from phosphate solutions has been further refined against a new and improved X-ray diffraction data set.The structures of T4 lysozyme in the crystals grown with polyethylene glycol as a precipitant, regardless of the sodium chloride concentration, were very similar to the structure in crystals grown from concentrated phosphate solutions. The main differences are related to the formation of mixed disulfides between cysteine residues 54 and 97 and 2-mercaptoethanol, rather than to the differences in the salt concentration in the crystal mother liquor. Formation of the mixed disulfide at residue 54 resulted in the displacement of Arg-52 and the disruption of the salt bridge between this residue and Glu-62.Other than this change, no obvious alterations in existing salt bridges in T4 lysozyme were observed. Neither did the reduction in the ionic strength of the mother liquor result in the formation of new salt bridge interactions. These results are consistent with the ideas that a crystal structure determined at high salt concentrations is a good representation of the structure at lower ionic strengths, and that models of electrostatic interactions in proteins that are based on crystal structures determined at high salt concentrations are likely to be relevant at physiological ionic strengths.
    Additional Material: 7 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100103
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    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100201
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    Computational studies of ligand diffusion in globins: I. Leghemoglobin (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 70-80 
    Details
    ISSN: 0887-3585
    Keywords: locally enhanced sampling ; molecular dynamics ; ligand penetration ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The thermally assisted diffusion of a small ligand (carbon monoxide) through a protein matrix (lupine leghemoglobin) is investigated computationally. The diffusion paths are calculated by a varient of the time-dependent Hartree approximation which we call LES (locally enhanced sampling). The variant which was recently introduced by Elber and Karplus1 is based on the classical TD-SCF approximation of Gerber et al.2 The simulation enables more significant search for diffusion pathways than was possible before. This is done by increasing the number of ligand trajectories using a single trajectory for the protein. We compare qualitatively diffusion rates in leghemoglobin and in myoglobin. The calculation shows that the diffusion in leghemoglobin is much faster than the diffusion in myoglobin, in agreement with experiment. The gate in leghemoglobin is opened by fluctuations at a close contact between the B/C and the G helices. The most relevant fluctuation is the rigid shift of the C helix with respect to the G helix. This path is not observed in a comparable calculation for myoglobin.1 This finding is rationalized by the lack of the D helix in leghemoglobin and a significantly more flexible CE loop. Supporting experimental evidence for the importance of the CE loop in leghemoglobin can be found in the kinetics studies of Gibson et al.28
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    URL: http://dx.doi.org/10.1002/prot.340100107
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    Calcium-free calmodulin is a substrate of proteases from human immunodeficiency viruses 1 and 2 (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 1-9 
    Details
    ISSN: 0887-3585
    Keywords: aspartyl protease ; HIV-1 and -2 proteases ; calmodulin ; specificity ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Calcium-free calmodulin-(CaM) is rapidly hydrolyzed by proteases from both human immunodeficiency viruses (HIV) 1 and 2. Kinetic analysis reveals a sequential order of cleavage by both proteases which initiates in regions of the molecule known from X-ray crystallographic analysis of Ca2+/CaM to be associated with calcium binding. Although HIV-1 and HIV-2 proteases hydrolyze two bonds in common, the initial site of cleavage required for subsequent events differs in each case. The first bond hydrolyzed by the HIV-1 protease in the Asn-Tyr linkage in the sequence,-N-I-D-G-D-G-Q-V-N-Y-E-E, found in the fourth calcium binding loop. In contrast, it is an Ala-Ala bond in the third calcium loop, -D-K-D-G-N-G-Y-I-S-A-A-E-, that is first hydrolyzed by the HIV-2 enzyme, followed in short order by cleavage of the same Asn-Tyr linkage described above. Thereafter, both enzymes proceed to hydrolyze additional peptide bonds, some in common, some not. Considerable evidence exists that inhibitors are bound to the protease in an extended conformation and yet all of the cleavages we observed occur within, or at the beginning of helices in Ca2+/CaM, regions that also appear to be insufficiently exposed for protease binding. Molecular modeling studies indicate that CaM in solution must adopt a conformation in which the first cleavage site observed for each enzyme is unshielded and extended, and that subsequent cleavages involve further unwinding of helices. The conclusion that the conformation of CaM is different from that of Ca2+/CaM is supported by the observation that Ca2+/CaM is resistant to hydrolysis by either enzyme. As well as demonstrating conformational differences between CaM and Ca2+/CaM, these studies provide further evidence that the two highly homologous human retroviral proteases may be distinguished enzymologically in terms of differential substrate specificities. In addition, some new and unpredicted sequences have been identified that undergo cleavage by these enzymes. Finally, the fact that an abundant, ubiquitous, and biologically important cellular protein is broken down by the HIV proteases could be physiologically relevant to HIV infection if the viral enzyme ever displays activity within the host cell.
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    URL: http://dx.doi.org/10.1002/prot.340100102
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    Structure of ricin A-chain at 2.5 Å (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 251-259 
    Details
    ISSN: 0887-3585
    Keywords: Ricin A-chain ; x-ray structure ; active site ; conserved residues ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Ricin has been refined in a crystallographic sense to 2.5 Å resolution and the model for the A-chain (RTA) is described in detail. Because RTA is the first member of the class of plant toxins to be analyzed, this model probably defines the major structural characteristics of the entire family of these medically important proteins. Explanations are provided to rationalize amino acids that are conserved between RTA and a number of homologous plant and bacterial toxins. Eight invariant residues appear to be involved in creating or stabilizing the active site. In the active site Arg180 and Glu177 are hydrogen bonded to each other and also coordinate a water molecule; each of these groups may be important in the N-glycosidation reaction. Several other polar residues may play lesser roles in the mechanism, including tyrosines 80 and 123 and asparagines 78 and 209. A number of conserved hydrophobic residues are seen to cluster within several patches and probably drive the overall folding of the toxin molecule.
    Additional Material: 6 Ill.
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    Site-directed mutagenesis of ricin A-chain and implications for the mechanism of action (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 270-278 
    Details
    ISSN: 0887-3585
    Keywords: ricin A ; site-directed mutagenesis ; mechanism of action ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Ricin A-chain is an N-glycosidase that attacks ribosomal RNA at a highly conserved adenine residue. The enzyme is representative of a large family of medically significant proteins used in the design of anticancer agents and in the treatment of HIV infection. The x-ray structure has been used as a guide to create several active site mutations by directed mutagenesis of the cloned gene. Glu177 is a key catalytic residue, and conversion to Gln reduces activity 180-fold. Asn209 is shown to participate in substrate binding by kinetic analysis. Conversion to Ser increases Km sixfold but has no effect on kcat. Conversion of Tyr80 and Tyr123 to Phe decreases activity by 15- and 7-fold respectively. A mechanism of action is proposed that involves binding of the substrate adenine in a syn configuration that resembles the transition state; the putative oxycarbonium ion is probably stabilized by interaction with Glu177.
    Additional Material: 6 Ill.
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    URL: http://dx.doi.org/10.1002/prot.340100311
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    Conformational changes in yeast phosphoglycerate kinase upon ligand binding: Fluorescence of a linked probe and chemical reactivity of genetically introduced cysteinyl residues (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 315-324 
    Details
    ISSN: 0887-3585
    Keywords: site-directed mutagenesis ; cysteine ; phosphoglycerate kinase ; IAEDANS ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The effects of ligands on the conformation of yeast phosphoglycerate kinase were explored by introducing cysteinyl residues at different positions in the molecule by site-directed mutagenesis. Thus several mutants were constructed, each containing a unique cysteinyl residue. Neither the conformation nor the enzyme activity was affected by the substitutions. The reactivity of the thiol groups and the fluorescence of N-acetyl-N′-(5-sulfo-1-naphtyl)ethylene-diamine covalently linked to these thiols were used to monitor the conformational changes induced upon ligand binding.It was found that the observed changes mainly involve the part of the protein located in the cleft, particularly the environment of residues 35 and 183. No alteration was observed on the external side of the protein. Only 3-Phosphoglycerate induced these conformational changes. However, when the fluorescent probe was attached to residue 377, the binding of the two substrates was required to induce a modification in the fluorescence of the probe. These results indicate that the substrates separately or together induce discrete molecular motions in phosphoglycerate kinase.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100405
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    Addendum (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 10 (1991), S. 359-359 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100408
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  • 94
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    The electrostatic potential of Escherichia coli dihydrofolate reductase (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 1-12 
    Details
    ISSN: 0887-3585
    Keywords: electrostatics ; enzyme-substrate interaction ; solvent screening ; active site potential ; structure-function relationship ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Escherichia coli dihydrofolate reductase (DHFR) carries a net charge of -10 electrons yet it binds ligands with net charges of -4 (NADPH) and -2 (folate or dihydrofolate). Evaluation and analysis of the electrostatic potential of the enzyme give insight as to how this is accomplished. The results show that the enzyme is covered by an overall negative potential (as expected) except for the ligand binding sites, which are located inside “pockets” of positive potential that enable the enzyme to bind the negatively charged ligands. The electrostatic potential can be related to the asymmetric distribution of charged residues in the enzyme.The asymmetric charge distribution, along with the dielectric boundary that occurs at the solvent-protein interface, is analogous to the situation occurring in superoxide dismutase. Thus DHFR is another case where the shape of the active site focuses electric fields out into solution.The positive electrostatic potential at the entrance of the ligand binding site in E. coli DHFR is shown to be a direct consequence of the presence of three positively charged residues at positions 32, 52, and 57-residues which have also been shown recently to contribute significantly to electronic polarization of the ligand folate. The latter has been postulated to be involved in the catalytic process. A similar structural motif of three positively charged amino acids that gives rise to a positive potential at the entrance to the active site is also found in DHFR from chicken liver, and is suggested to be a common feature in DHFRs from many species. It is noted that, although the net charges of DHFRs from different species vary from +3 to -10, the enzymes are able to bind the same negatively charged ligands, and perform the same catalytic function.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110102
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    Erratum (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 77-77 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110109
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    Sesam: A relational database for structure and sequence of macromolecules (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 59-76 
    Details
    ISSN: 0887-3585
    Keywords: protein structure ; amino acid sequence ; database ; macromolecules ; molecular modeling ; knowledge base ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A system is described that provides ways of integrating data on protein structure, sequence, and survey results, with molecular graphics and molecular mechanics software. Its major component is the relational database SESAM, presently implemented under the commercial package SYBASE. By desin, the database allows full integration - within the same data organization - of raw data on protein structure, sequence, ligands, and heterogroups, obtained from the Brookhaven Protein Databank, with pure sequence information available from other databanks such as SWISS-PROT. It contains in addition higher level descriptions of structural and topological properties, as well as survey results, obtained by executing specialized computer programs. Aside from the very useful attribute of closely combining structural and nonstructural information, other important features distinguish it from analogous systems developed elsewhere. It includes a molecular dictionary with complete description of geometric properties and energy parameters used in modeling and conformational energy calculations. Using this dictionary, structural data are validated by checking for localized inconsistencies in atomic coordinates, atomic symbols, chirality definitions, and flagging errors and incomplete entries. Because of both the dictionary and the validation procedures, SESAM can be readily interfaced with conventional molecular graphics and mechanics software packages, or with other specialized application programs. With the aid of appropriate interfaces, data access is sufficiently fast for SESAM to be interrogated interactively. Prototypes of user interfaces, as well as an interface with the molecular graphics package BRUGEL, are described and the power of the system is illustrated in applications such as homology-based protein modeling, computer-aided protein design, protein structure predictions, analysis of local structure motifs, and of relationships between protein sequence and structure.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110108
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  • 97
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    An autoantibody to single-stranded DNA: Comparison of the three-dimensional structures of the unliganded fab and a deoxynucleotide-fab complex (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 159-175 
    Details
    ISSN: 0887-3585
    Keywords: anti-ss-DNA autoantibody ; deoxynucleotide-Fab complex ; conformational changes in protein when ligand is bound ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Crystal structures of the Fabs from an autoantibody (BV04-01) with specificity for single-stranded DNA have been determined in the presence and absence of a trinucleotide of deoxythymidylic acid, d(pT)3. Formation of the ligand-protein complex was accompanied by small adjustments in the orientations of the variable (VL and VH) domains. In addition, there were local conformational changes in the first hypervariable loop of the light chain and the third hypervariable loop of the heavy chain, which together with the domain shifts led to an improvement in the complementarity of nucleotide and Fab. The sugar-phosphate chain adopted an extended and “open” conformation, with the base, sugar, and phosphate components available for interactions with the protein. Nucleotide 1 (5′-end) was associated exclusively with the heavy chain, nucleotide 2 was shared by both heavy and light chains, and nucleotide 3 was bound by the light chain. The orientation of phosphate 1 was stabilized by hydrogen bonds with serine H52a and asparagine H53. Phosphate 2 formed an ion pair with arginine H52, but no other charge-charge interactions were observed. Insertion of the side chain of histidine L27d between nucleotides 2 and 3 resulted in a bend in the sugar-phosphate chain. The most dominant contacts with the protein involved the central thymine base, which was immobilized by cooperative stacking and hydrogen bonding interactions. This base was intercalated between a tryptophan ring (no. H100a) from the heavy chain and a tyrosine ring (no. L32) from the light chain. The resulting orientation of thymine was favorable for the simultaneous formation of two hydrogen bonds with the backbone carbonyl oxygen and the side chain hydroxyl group of serine L91 (the thymine atoms were the hydrogen on nitrogen 3 and keto oxygen 4).
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110302
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    Masthead (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991) 
    Details
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110401
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  • 99
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    Changes in the electron density of the cofactor NADPH on binding to E. coli dihydrofolate reductase (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 263-270 
    Details
    ISSN: 0887-3585
    Keywords: protein-ligand interactions ; electrostatics ; density functional theory ; protein structure-function relationship ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Quantum-mechanical electron density calculations reveal that a significant polarization is induced in the cofactor NADPH (reduced nicotinamide adenine dinucleotide phosphate) on binding to the enzyme dihydrofolate reductase. The calculations indicate that electron density corresponding to ∼0.7 electron charges is shifted within the molecule, extending over more than 20Å. Further calculations on proposed enzyme mutants show that the polarization of NADPH on binding to DHFR is, in large part, induced by a motif of three positively charged residues. This motif was also identified to be directly responsible for the positive electrostatic potential surrounding the cofactor binding site in the enzyme. The possibility of this long-range polarization of NADPH was originally proposed based on a previous study of ligand binding to DHFR where a conserved structural motif of three positively charged residues was found to play a major role in polarizing the substrate folate over its entire length of 18 Å.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110405
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  • 100
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    Crystal parameters and molecular replacement of an anticholera toxin peptide complex (1991)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 11 (1991), S. 218-222 
    Details
    ISSN: 0887-3585
    Keywords: antibody ; Fab ; antigen ; crystallization ; x-ray crystallography ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: TE33 is an Fab fragment of a monoclonal antibody raised against a 15-residue long peptide (CTP3), corresponding in sequence to residues 50-64 of the cholera toxin B subunit. Crystals of the complex between TE33 and CTP3 have been grown from 20% (w/v) polyethylene glycol-8000 at pH 4.0. The crystals are orthorhombic, space group P21212, with unit cell dimensions a = 104.15, b = 110.61, and c = 40.68 Å. X-Ray data have been collected to a resolution of 2.3 Å. The asymmetric unit contains one molecule of Fab and one molecule of CTP3. The presence of CTP3 has been demonstrated by fluorescence quenching of the dissolved crystal after X-ray data collection. A molecular replacement solution was found based on the coordinates of DB3, an antiprogesterone Fab fragment.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340110306
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