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  • 1
    Electronic Resource
    Electronic Resource
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340100105
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  • 2
    Electronic Resource
    Electronic Resource
    Structures of the “open” and “closed” state of trypanosomal triosephosphate isomerase, as observed in a new crystal form: Implications for the reaction mechanism (1993)
    New York, NY : Wiley-Blackwell
    Proteins: Structure, Function, and Genetics 16 (1993), S. 311-326 
    Details
    ISSN: 0887-3585
    Keywords: triosephosphate isomerase ; TIM ; X-ray crystallography ; binding studies ; crystal packing ; conformational change ; reaction mechanism ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The structure of trypanosomal triosephosphate isomerase (TIM)has been solved at a resolution of 2.1Å in a new crystal form grown at pH 8.8 from PEG6000. In this new crystal form (space group C2, cell dimensions 94.8 Å, 48.3 Å, 131.0 Å, 90.0°, 100.3°, 90.0°), TIM is present in a ligand-free state. The asymmetric unit consists of two TIM subunits. Each of these subunits is part of a dimer which is sitting on a crystallographic twofold axis, such that the crystal packing is formed from two TIM dimers in two distinct environments. The two constituent monomers of a given dimer are, therefore, crystallographically equivalent. In the ligand-free state of TIM in this crystal form, the two types of dimer are very similar in structure, with the flexible loops in the “Open” conformation. For one dimer (termed molecule-1), the flexible loop (loop-6) is involved in crystal contacts. Crystals of this type have been used in soaking experiments with 0.4 M ammonium sulphate (studied at 2.4 Å resolution), and with 40 μM phosphoglycolohydroxamate (studied at 2.5 Å resolution). It is found that transfer to 0.4 M ammonuum sulphate (equal to 80 times the Ki of sulphate for TIM), gives rise to significant sulphate binding at the active site of one dimer (termed molecule-2), and less significant binding at the active site of the other. In neither dimer does sulphate induce a “closed” conformation. In a mother liquor containing 40 μM phosphoglycolohydroxamate (equal to 10 times the Ki of phosphoglycolohydroxamate for TIM), an inhibitor molecule binds at the active site of only that dimer of which the flexible loop is free from crystal contacts (molecule-2). In this dimer, it induces a closed conformation. These three structures are compared and discussed with respect to the mode of binding of ligand in the active site as well as with respect to the conformational changes resulting from ligand binding. © 1993 Wiley-Liss, Inc.
    Additional Material: 13 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/prot.340160402
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  • 3
    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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  • 4
    Electronic Resource
    Electronic Resource
    Design and Synthesis of Dynemicin Analogs (1999)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1999 (1999), S. 1-13 
    Details
    ISSN: 1434-193X
    Keywords: Dynemicin ; Enediynes ; Antitumor agents ; Antibiotics ; Cross-coupling ; Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: -Dynemicin A is a member of the family of enediyne natural products. It is unique in that it combines a ten-membered enediyne with an anthraquinone substructure. These features stimulated the development of synthetic approaches to the natural product itself and of analogs thereof. This review summarizes the total syntheses of dynemicin A. In addition, an overview of the known analogs is presented. The analogs can be classified according to the designed trigger mechanism. Most of the analogs contain a removable carbamate on the nitrogen atom. Others are quite similar to the natural lead in that they contain a quinone substructure, which upon reduction causes opening of the oxirane ring. In addition, there are analogs that contain an aromatic sector, the enediyne, and the oxirane ring but lack the nitrogen heterocycle. In these compounds the aryl ring assumes a different conformation from that in dynemicin A. Many of the simplified analogs proved to be quite active in vitro as well in vivo against murine tumor models. A highlight is compound 30 which is much more active than dynemicin A itself. However, looking at all analogs there is no clear-cut correlation between the DNA-cleaving ability at neutral pH and the in vitro results. From this one might conclude that there are possibly two mechanisms for antitumor activity. One involves diradical formation whereas the other might be due to a ligand-receptor interaction.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Struktur und Eigenschaften einer neuen PolyesterfaserNach einem Vortrag auf der Tagung der GDCh-Fachgruppe „Kunststoffe und Kautschuk“ am 10. April 1962 in Bad Nauheim. (1962)
    Weinheim : Wiley-Blackwell
    Zeitschrift für die chemische Industrie 74 (1962), S. 624-628 
    Details
    ISSN: 0044-8249
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Poly-[1.4-bis-(hydroxymethyl)-cyclohexan-terephthalat] kann das cis- und das trans-Isomer der Cyclohexan-Komponente enthalten. Die Abhängigkeit der Eigenschaften des Polymeren vom cis/trans-Verhältnis wird untersucht. Die Kristallgitter der Polymeren mit nur einem Isomeren in der Kette gehen bei Änderung des cis/trans-Verhältnisses kontinuierlich ineinander über. Ein eutektisches Gemisch tritt nicht auf. Gegenwärtig werden Fasern mit einem cis/trans-Verhältnis von etwa 1:2 hergestellt. Sie sind gegen Wasser nur sehr wenig empfindlich, ihre Arbeitsrückgabe ist groß.
    Additional Material: 10 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/ange.19620741606
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  • 6
    Electronic Resource
    Electronic Resource
    Extracellular matrix receptors, ECMRII and ECMRI, for collagen and fibronectin correspond to VLA-2 and VLA-3 in the VLA family of heterodimers (1988)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 37 (1988), S. 385-393 
    Details
    ISSN: 0730-2312
    Keywords: cell adhesion ; arg-gly-asp amino acid sequence ; VLA proteins ; integrin superfamily ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The Very Late Activation Antigen (VLA) proteins are a family of five related heterodimers, which also are part of the integrin superfamily of cell adhesion molecules. Except for the identification of VLA-5 as a fibronectin receptor structure, the functions of the VLA proteins have remained unclarified. In this paper, immuno-precipitation experiments with both anti-α and anti-β subunit antibodies showed that the previously identified cell adhesion receptor for collagen, extracellular matrix receptor II (ECMRII), is equivalent to VLA-2. At the same time a previously described multispecific cell adhesion receptor for collagen, fibroncclin, and laminin (ECMRI) has been shown to be identical to VLA-3. Although the mAb 12F1 and P1H5 both recognized VLA-2 (ECMRII), they appeared to define distinct epitopes on the α2 subunit. On the other hand, the mAb PIB5 and J143 recognized the α3 subunit of VLA-3 (ECMRI) at or near the same site. Consistent with the collagen receptor functions of VLA-2 (ECMRII) and VLA-3 (ECMRI), anti-VLA β antiserum blocked cell attachment to collagen.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240370406
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  • 7
    Electronic Resource
    Electronic Resource
    β1 integrin cytoplasmic domain regulates the constitutive conformation detected by MAb 15/7, but not the ligand-induced conformation (1998)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 71 (1998), S. 63-73 
    Details
    ISSN: 0730-2312
    Keywords: integrin ; activation epitopes ; ligand binding ; focal adhesions ; cytoplasmic domains ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The anti-integrin β1 MAb 15/7 sometimes may be a reporter of integrin activation or ligand occupancy. However, certain β1 tail deletions eliminate ligand binding despite inducing maximal constitutive 15/7 expression [Puzon-Mclaughlin et al. (1996): J Biol Chem 271:16580-16585]. Here we describe β1 tail mutations (e.g., double point mutations [D759L/F763L, F766L/E769L], or replacement of the β1 tail by the β5 tail) that prevent rather than induce constitutive appearance of the 15/7 epitope. Despite variable losses of constitutive 15/7 epitope, these mutants all retained a similar inducible 15/7 epitope component as seen upon incubation with GRGDSP peptide ligand. In addition, constitutive 15/7 expression did not correlate with integrin localization into focal adhesions. In conclusion, we show for the first time for a fully functional integrin that specific mutations within the β1 tail can down-regulate the constitutive appearance of an extracellular conformation defined by MAb 15/7. Because this regulation occurs away from the ligand binding site and does not correlate with responsiveness to integrin ligand, cell adhesion, or localization into focal adhesions, a novel type of conformational regulation is suggested. J. Cell. Biochem. 71:63-73, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Human prostate cancer model: Roles of growth factors and extracellular matrices (1992)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 50 (1992), S. 99-105 
    Details
    ISSN: 0730-2312
    Keywords: extracellular matrices (ECMs) ; bFGF ; NGF ; HGF and KGF ; growth factors (GFs) ; human prostate cancer model ; prostate cancer-bone interaction ; stromal-epithelial interaction ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: A human prostate cancer model was established by inoculating a prostate specific antigen (PSA)-producing LNCaP cell line with either prostate or bone fibroblasts. Alternatively, this human prostate cancer model can also be established by inoculating LNCaP cell with growth factor(s) (GFs) and extracellular matrix (ECM) immobilized on Gelfoam®. The resulting LNCaP tumors were used to evaluate PSA production and excretion athymic hosts. This model was also employed to examine the biochemical nature of mesenchymal cell-derived growth-promoting protein(s) and to assess the efficacy of potential chemotherapeutic agents. Because of the propensity of human prostate cancer to metastasize to the bone, this study defined a 1.0 M NaCI-eluted fraction, MS1, from the conditioned medium of a bone stromal cell line (MS) by heparin-affinity column chromatography. The growth-promoting activity was assayed both in vivo (e.g., tumor formation) and in vitro (e.g., soft agar colony formation). We found that the growth-promoting activity was trypsin-and heat-sensitive, and partially degraded by acid and dithiothreitol. Immunochemical studies indicated that the polyclonal antibody raised against MS1 blocked the growth-promoting effect elicited by the bone-conditioned media. This growth-promoting factor was found to be immunochemically dissimilar to KGF, HGF, and bFGF. However, addition of bFGF, HGF and NGF, but not a FGF, TGFβ, IGF1, IGF2, PDGF, EGF, TGFα and KGF, stimulated anchorage-independent growth of prostate cells, a condition closely parallel to tumor formation in vivo. We found that the MS1 fraction also contained fibronectin and tenascin but not laminin or collagen IV. None of the ECM proteins induced soft agar colony formation by normal prostate epithelial cells. Therefore, it is possible that the ECM protein(s) may potentiate the tumor-inducing activity of locally produced GFs. © 1992 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jcb.240501222
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  • 9
    Electronic Resource
    Electronic Resource
    Butyrate analogue, isobutyramide, inhibits tumor growth and time to androgen-independent progression in the human prostate LNCaP tumor model (1998)
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 69 (1998), S. 271-281 
    Details
    ISSN: 0730-2312
    Keywords: butyrate ; isobutyramide ; prostate cancer ; LNCaP ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Progression to androgen independence remains the main obstacle to improving survival and quality of life in patients with advanced prostate cancer. Induction of differentiation may serve as a rational basis for prevention of progression to androgen independence by modulating gene expression activated by castration or upregulated during androgen-independent progression. The objectives of this study were to characterize the in vitro effects of sodium butyrate on human prostate cancer cell growth, PSA gene expression, and differentiation in the LNCaP tumor model and to determine whether tumor progression in vivo is delayed by isobutyramide, an orally bioavailable butyrate analogue with a longer half-life. The effects of isobutyramide on LNCaP tumor growth and serum PSA levels in both intact and castrate male mice were compared to controls. At concentrations 〉 1 mM, butyrate induced dose-dependent changes towards a more differentiated phenotype, G1 cell cycle arrest, and an 80% decrease in LNCaP cell growth rates. PSA gene expression was increased threefold by butyrate, indicative of differentiation-enhanced gene expression. The half-life of isobutyramide in athymic mice was determined by gas chromatography to be 4 h. During a 4 week period in intact-placebo mice, tumor volume and serum PSA increased 4.1- and 6.6-fold, respectively, compared to twofold and 2.7-fold increases in tumor volume and serum PSA in intact-treated mice. During a 7 week period in castrate-placebo mice, tumor volume and serum PSA levels increased 2.4-fold and fourfold, respectively, compared to a 50% reduction in tumor volume and a twofold increase in serum PSA above nadir levels in castrate mice treated with adjuvant isobutyramide. Isobutyramide treatment induced pronouced morphological changes in LNCaP tumor cells, with loss of defined nucleoli and dispersion of chromatin distribution. LNCaP tumor PSA mRNA levels actually increased threefold, indicative of differentiation-enhanced gene expression. This study demonstrates that butyrate causes LNCaP cell cycle arrest and increased PSA gene expression, both indicative of differentiation. The combination of castration and adjuvant isobutyramide was synergistic in delaying tumor progression. Decreased tumor cell proliferation and increased PSA gene expression induced by isobutyramide results in disconcordant changes in serum PSA and tumor volume and reduces the utility of serum PSA as a marker of response to therapy. J. Cell. Biochem. 69:271-281, 1998. © 1998 Wiley-Liss, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Cycloaddition Reactions in Carbohydrate Chemistry. (Reihe: ACS Symposium Series, Vol. 494, Reihenherausgeber: M. J. Comstock, Herausgegeben von R. M. Giuliano. American Chemical Society, Washington DC, 1992. X, 181 S., geb. 49.95$. - ISBN 0-8412-2429-3 (1993)
    Weinheim : Wiley-Blackwell
    Zeitschrift für die chemische Industrie 105 (1993), S. 1271-1272 
    Details
    ISSN: 0044-8249
    Keywords: Chemistry ; General Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/ange.19931050849
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