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  • 1995-1999  (2,304)
  • 1940-1944
  • 1997  (2,304)
  • Biochemistry and Biotechnology  (1,317)
  • Cell & Developmental Biology  (441)
  • Chemical Engineering  (418)
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  • 1995-1999  (2,304)
  • 1940-1944
Year
  • 101
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 131 (1997), S. 388-393 
    ISSN: 1432-2072
    Keywords: Key words Carteolol hydrochloride ; β-Blocker ; Penetrability ; Brain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To elucidate the penetrability of carteolol, a β-adrenoceptor antagonist (β-blocker) into the brain of rats, intracerebral and serum concentrations of the compound were determined in male rats receiving single or repetitive oral administration of carteolol hydrochloride at 30 mg/kg. The time-course of the intracerebral concentration of carteolol following single IV administration of the compound at 10 and 30 mg/kg was also studied in male rats. A high-performance liquid chromatography method was used to determine the intracerebral and serum concentrations. Following single oral dosing, the intracerebral concentration of carteolol reached a maximum of 0.074 μg/g at 2 h postdosing and declined with a half-life of 3.7 h, and the Cmax and AUC of carteolol in the brain were 12.5% and 19.8% of those in serum. The intracerebral and serum concentrations of carteolol were determined in male rats receiving repetitive oral dosing of the compound once daily for 7 days. The concentration of carteolol in the brain and serum at 1 h postdosing varied within a range of 0.059–0.091 μg/g and 0.321–0.443 μg/ml, respectively, throughout the dosing period, showing no changes in the penetrability of the compound into the brain due to repeated dosing. The concentration of carteolol in the brain and serum increased in a dose-dependent manner in rats receiving a single IV administration of the compound. The elimination half-life of carteolol in the serum and brain was 0.6–0.8 h and 1.3–1.7 h, respectively, in rats following single IV dosing of the compound. The half-life in the brain was about twice as long as that in the serum. The brain to serum concentration ratio was 0.306:0.499. From the above results, it was concluded that carteolol is distributed from the circulation to the brain with low penetrability.
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  • 102
    ISSN: 1432-2072
    Keywords: Key words Imipramine ; Serotonin ; Raphe nuclei ; Prefrontal cortex ; Microdialysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effect of acute administrations of three doses of imipramine (1, 5 and 10 mg/kg SC), a widely used tricyclic antidepressant, on extracellular levels of serotonin (5-HT) has been studied by intracerebral microdialysis in raphe nuclei and prefrontal cortex of conscious rats. Imipramine 1 mg/kg SC did not change extracellular 5-HT in either raphe nuclei and prefrontal cortex. However, with the dose of 5 mg/kg SC imipramine induced in raphe nuclei, a brief increase of extracellular 5-HT followed by a lowering (55–65% basal release) of the neurotransmitter. The same dose of imipramine decreased (60–70% of basal value) extracellular 5-HT in prefrontal cortex. Imipramine 10 mg/kg SC significantly increased 5-HT levels in both raphe nuclei (190 ± 20% above basal value) and prefrontal cortex (280 ± 15% above basal value). Pretreatment with (-)pindolol (5 mg/kg SC), a non-selective 5-HT1A subtype receptor antagonist, 30 min before imipramine 5 mg/kg, modified the effect of the antidepressant: an increase, instead of a decrease, on prefrontal cortex dialysate 5-HT was observed. (-)Pindolol (10 mg/kg SC) increased extracellular 5-HT in both raphe nuclei (155 ± 20% above basal value) and prefrontal cortex (160 ± 8% above basal value). These data show that acute administration of imipramine modifies extracellular 5-HT at the level of the raphe nuclei and prefrontal cortex. 5-HT1A autoreceptors in the raphe nuclei, which this study suggests to be tonically active, may be stimulated after systemic administration of high doses of imipramine.
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  • 103
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    Springer
    Pflügers Archiv 434 (1997), S. 438-444 
    ISSN: 1432-2013
    Keywords: Key words Baroreceptor reflex ; Nucleus tractus solitarii ; Neonatal ; Maturation ; Cardiac vagal tone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Ontogenesis of both vagal control of heart rate and the baroreceptor vagal reflex were evaluated in rats at postnatal ages (P) of 5/6, 10, 15, 20, 25 and 〉42 days anaesthetised with urethane (1.5 g/kg). Between P5/6 and P25 heart rate rose from 372 ± 12 to 448 ± 20 beats per minute and mean arterial pressure increased from 33.9 ± 3.1 to 74.59 ± 3.25 mm Hg (mean ± SEM, n = 7 and 11 respectively). Cardiac vagal tone was absent at P10 but significant at P20 (P 〈 0.05) as revealed with atropine (0.5–1 mg/kg i.v.). Baroreceptor cardiac reflex sensitivity, tested with phenylephrine (10–50 μg/kg i.v.), was attenuated significantly in P10–20 rats compared with P5/6, P25 and mature animals. In P14–17 rats stimulation of neurones in either the solitary tract or ambiguual nuclei, by microinjection of L-glutamate (100–200 pmol), evoked an atropine-sensitive bradycardia indicating a functional integrity of central and peripheral efferent pathways mediating the baroreceptor reflex. Thus, the baroreceptor vagal reflex is functional in P5/6 rats but becomes attenuated between P10–P20, which is coincident with the maturational rise in arterial pressure.
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  • 104
    ISSN: 1432-2013
    Keywords: Key words Baroreceptor reflex ; Rostral ventrolateral medulla ; C1 cell group ; In vivo voltammetry ; Sino-aortic deafferentation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To test in a catechol-specific and dynamic manner for the existence of a powerful long-lasting inhibition arising from barosensitive afferents that depresses the activity of adrenergic neurons in the rostral ventrolateral medulla (RVLM), in vivo voltammetry was used before and after acute sino-aortic deafferentation. Rats were anaesthetized with pentobarbital or halothane and ventilated with a mixture of air and oxygen. Snares were inserted around the vagus, the glossopharyngeal and the superior laryngeal nerves. After placing the animal prone in the stereotaxic frame and stabilization at a high mean arterial pressure (MAP ≈ 120 mmHg), the snares were rapidly closed to produce complete barodeafferentation, assessed by loss of heart rate responses and changes in renal nerve sympathetic activity in response to vasoactive agents. Recording of a catechol signal was maintained in the RVLM during deafferentation. Under pentobarbital-induced anaesthesia (n = 5), deafferentation did not lead to a significant change in the catechol signal within the deafferented group. Under halothane-induced anaesthesia and phenylephrine-induced high baseline pressure (n = 5), no changes in the catechol signal were observed upon deafferentation (not significant vs sham animals: n = 5). This failure to demonstrate a major increase in catechol activity upon deafferentation does not fit with the hypothesis that a powerful tonic baroreflex-mediated inhibition depresses the activity of adrenergic RVLM barosensitive bulbospinal neurons, even when the baseline MAP is high. Rather, these data are compatible with weak or no inhibition of catechol activity by the baroreceptors and a nonessential role of adrenergic neurons within the baroreceptor reflex arc itself: the adrenergic neurons may not be in series within this arc but in parallel with the arc. This interpretation is in keeping with newer schemas of autonomic core circuitry that are devoid of adrenergic neurons.
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  • 105
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    Psychopharmacology 130 (1997), S. 79-84 
    ISSN: 1432-2072
    Keywords: Key words Latent inhibition ; Conditioned emotional response ; Amphetamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of a single administration of d-amphetamine (0.32 mg/kg, SC) upon latent inhibition (LI) in a one-session pre-exposure and conditioning procedure was investigated in rats in a conditioned emotional response paradigm. It was found that amphetamine attenuated LI. The effects could not be attributed to differences in unconditioned suppression nor to differences in response rates between the experimental groups. These results support the observations of Dunn and suggest that the disruption of LI may not depend upon a complex interaction between changes in neuronal processes consequent upon repetitive amphetamine administration and the schedule with which the drug is administered during the experimental procedure.
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  • 106
    ISSN: 1432-2072
    Keywords: Key words Working memory ; Motor activity ; Serotonergic ; Muscarinic ; Nicotinic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular adminstration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats.
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  • 107
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Prepulse inhibition ; Schizophrenia ; Dopamine ; Serotonin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The β-adrenoceptor antagonist as well as serotonin 5-HT1 receptor antagonist, (−)alprenolol, was found to potentiate the disrupting effect of the non-competitive NMDA receptor antagonist, dizocilpine, on prepulse inhibition (PPI) of the acoustic startle response (ASR) in the rat. The facilitating effect of dizocilpine on ASR amplitude was also potentiated by (−)alprenolol. (−)Alprenolol by itself did not affect either of these measures. These effects did not seem to be related to the unselective β-adrenoceptor antagonist property of (−)alprenolol, since combined pretreatment with the β1- and β2-adrenoceptor antagonists, metoprolol and ICI 118551, did not alter the effects of dizocilpine on startle behaviour. However, a serotonergic influence was suggested by the fact that a facilitating effect of dizocilpine on ASR amplitude was also obtained by pretreatment with the 5-HT precursor, L-5-HTP, in benserazide-pretreated rats. Furthermore, pretreatment with the 5-HT2 selective receptor antagonist, MDL 100907, significantly reduced the (−)alprenolol-induced potentiation of the effects of dizocilpine on startle behaviour, while the 5-HT3 selective receptor antagonist, ondansetron, failed to do that. Finally, the (−)alprenolol-induced potentiation of the effects of dizocilpine was significantly reduced by pretreatment with the atypical antipsychotic, clozapine, and by the potential antipsychotic and selective dopamine D2 receptor antagonist, raclopride. This study suggests that altered 5-HT activity may influence the effects of psychotomimetic drugs such as dizocilpine on sensorimotor function, and this observation may have implications for the pharmacological treatment of schizophrenia in humans.
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  • 108
    ISSN: 1432-2072
    Keywords: Key words Hyperactivity ; Hippocampus ; Neonate ; Negative symptoms ; Positive symptoms ; Rat ; Schizophrenia ; Social behaviour
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 μmol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.
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  • 109
    ISSN: 1432-2072
    Keywords: Key words AMPA ; NBQX ; Behavioral sensitization ; Cocaine ; Amphetamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  We examined the effect of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, on the development and expression of behavioral sensitization to amphetamine and cocaine in rats. A single injection of NBQX (12.5 mg/kg) administered 30 min prior to cocaine during the induction phase (days 1–5) prevented the development of cocaine sensitization, assessed by responsiveness to cocaine challenge on day 8. This NBQX regimen did not affect development of amphetamine sensitization. Two pretreatment injections of NBQX, one 20 min before and one 70 min after amphetamine on each day of the induction phase (days 1–6), did not affect sensitization of stereotypy but prevented sensitization of post-stereotypy ambulatory hyperactivity (both assessed by responsiveness to amphetamine challenge on day 8). The effect of NBQX on ambulatory sensitization was dose-dependent (attenuation with 12.5 mg/kg, complete prevention with 25 mg/kg). In contrast to its effects on development, NBQX (25 mg/kg) did not prevent expression of sensitization to cocaine or amphetamine. NBQX itself exerted no significant effects on locomotor activity in either drug-naive rats or rats that had received either NBQX or amphetamine repeatedly. These findings support a requirement for AMPA receptor stimulation in the development of locomotor sensitization to cocaine and amphetamine, but suggest a different mechanism for sensitization of amphetamine stereotypy.
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  • 110
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    Psychopharmacology 133 (1997), S. 383-388 
    ISSN: 1432-2072
    Keywords: Key words Intracranial self stimulation (ICSS) ; Dopamine ; Rat ; GABA transaminase inhibitor ; Vigabatrin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Gamma-vinyl GABA (GVG, also referred to as vigabatrin), an irreversible inhibitor of GABA transaminase (GABA-T), raises levels of GABA in nerve terminals, inhibits striatal dopamine release, and attenuates cocaine-induced increases in extracellular dopamine in the striatum and nucleus accumbens. In order to determine the action of GVG on dopamine-mediated reward, we examined its effects on the threshold for rewarding brain stimulation in male F-344 rats. GVG dose-dependently raised brain stimulation reward (BSR) thresholds at doses of 200, 300, and 400 mg/kg without significant effects on motor performance as measured by response latencies. In order to determine if GVG had similar modulatory effects on cocaine-induced lowering of BSR thresholds, the effective doses of GVG were co-administered with 2.5 and 5.0 mg/kg cocaine, doses that significantly lower BSR thresholds. The 400 mg/kg dose of GVG significantly blocked the lowering of thresholds seen at each dose of cocaine. Cocaine in combination with 200 or 300 mg/kg GVG, doses of GVG that significantly raise BSR thresholds, resulted in thresholds not significantly different from those obtained with cocaine alone. These data demonstrate that, at the doses tested, GVG is more effective at modulating basal reward thresholds than at modulating thresholds lowered by cocaine, implying that as dopaminergic activity increases, GABAergic activity must also increase in order to exert its inhibitory influence on dopaminergic activity.
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  • 111
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    Psychopharmacology 134 (1997), S. 221-229 
    ISSN: 1432-2072
    Keywords: Key words Behavioral sensitization ; Dopamine ; Amphetamine ; Rat ; Microdialysis ; Caudate putamen ; Nucleus accumbens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The repeated administration of amphetamine (AMPH) results in a pattern of behavioral changes which includes an augmentation of some behaviors, generally referred to as behavioral sensitization. Some investigators have suggested that an increased dopamine (DA) response to AMPH challenge may underlie behavioral sensitization, while others have reported behavioral sensitization in the absence of an enhanced DA response. Because temporal and dosage parameters of the AMPH pretreatment regimen have been suggested to play a role in the appearance of an enhanced DA response, we utilized a variety of AMPH pretreatment regimens to assess the relationship between pretreatment dose of AMPH, duration of withdrawal and the DA response in caudate-putamen and nucleus accumbens to a subsequent AMPH challenge. Under our experimental conditions, behavioral sensitization was observed after each of these treatments in the absence of an enhanced DA response in either brain region.
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  • 112
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    Psychopharmacology 134 (1997), S. 319-329 
    ISSN: 1432-2072
    Keywords: Key words Animal model of depression Chronic mild stress ; Predictive validity ; Face validity Construct validity ; Reliability ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.
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  • 113
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    Transplant international 10 (1997), S. 103-108 
    ISSN: 1432-2277
    Keywords: Key words Liver transplantation ; rat model ; Rat ; liver transplantation ; fine needle aspiration ; Fine needle aspiration ; liver ; rat ; Rejection ; liver ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rat models are often used to study liver allograft rejection. We have established a model for rat liver allograft rejection, monitored by fine needle aspiration biopsy (FNAB), in the strain combination PVG-to-BN with a mean survival time of 37 ± 20 days. In this model, we observed acute rejection with an intense peak of lymphoid blasts and lymphocyte-dominated inflammation in the FNAB [9.1 ± 3.0 corrected increment units (CIU)], and an eventual increase in macrophages (up to 4.2 ± 4.4 CIU), together with fibrosis and parenchymal necrosis in the graft. Markers of immune activation, such as an increase in IL-2-receptor (from 1 % ± 2 % to 21 % ± 13 %) and class II (from 20 % ± 9 % to 43 % ± 13 %) expressing lymphoid cells and induction of ICAM-1 in the graft, were consistent with the overall cellular response. The FNAB correlated well with parallel graft histology. In this rat model, the atraumatic monitoring makes a close follow-up possible without having to sacrifice the experimental animals. This saves work, animals, and costs in the study of liver rejection.
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  • 114
    ISSN: 1432-2277
    Keywords: Key words Liver transplantation ; passenger leukocytes ; rat ; Passenger leukocytes ; liver transplantation ; rat ; Rat ; liver transplantation ; passenger leukocytes ; Tolerance ; liver transplantation ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The tolerance induced by orthotopic liver transplantation [DA (RT1a) rats to PVG (RT1c) rats] can be prevented by total body irradiation of the donor rat. Reconstitution of the irradiated donor with DA splenic leukocytes reintroduces this tolerance. To investigate the major histocompatibility complex (MHC) specificity of passenger leukocytes, irradiated DA donors were reconstituted by third-party BN (RT1n) splenic leukocytes. The reconstitution with BN splenocytes re-established DA-specific tolerance in PVG recipients, as confirmed by subsequent DA cardiac allografting, while BN hearts were rejected with second-set tempo. To determine which cell components play an important role in re-establishing liver graft tolerance, DA splenic leukocytes were further purified into three types: T, B, and adherent cells. Only “T-cell-enriched” preparations restored liver graft tolerance in three out of five PVG recipients. These results suggest that passenger leukocytes of differing MHC types can help to induce liver-specific tolerance and that T cells in the liver graft may be essential to regulate tolerance induction.
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  • 115
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    Transplant international 10 (1997), S. 386-391 
    ISSN: 1432-2277
    Keywords: Key words Intestinal transplantation ; function ; rat ; Small bowel function ; intestinal transplantation ; rat ; Rat ; small bowel function ; intestinal transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Successful small bowel transplantation requires normal functional capacity of the graft and unaltered metabolism of the host. Weight gain and wet weight of muscle groups and intra-abdominal fat pads were compared between transplanted, sham-operated, short bowel-operated, and normal rats that were fed either standard chow or fat-enriched (15 %) pellets. Weight gain and wet weight of muscle groups and fat pads for the control, transplanted, and sham-operated rats were identical, while short bowel animals showed reduced weight. Transplanted rats receiving fat-enriched food had lower wet weight of fat pads than control animals on the high-fat diet. We conclude that small bowel transplantation makes it possible to overcome the intestinal failure associated with short bowel syndrome, leading to overall normal weight gain and development of the recipient. However, altered fat metabolism, reflected in changed body composition, was observed in transplanted animals on the high-fat diet.
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  • 116
    ISSN: 1432-2277
    Keywords: Key words Immunosuppression ; FTY 720 ; rat ; small bowel transplantation ; FTY 720 ; immunosuppression ; rat ; small bowel transplantation ; Rat ; small bowel transplantation ; FTY 720 ; Small bowel transplantation ; rat ; FTY 720
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present study, we examined the immunosuppressive effect of a new drug, FTY 720, on small bowel transplantation (SBT) in rats. Grafts from (LEW × BN) F 1-to-LEW rats treated with FTY 720 at 0.5 mg/kg from day 0 to 14 post-SBT survived significantly longer than untreated grafts. In addition, the administration of FTY 720 combined with cyclosporin (CyA; 5 mg/kg per day) had a synergistic effect on allograft survival. The graft-versus-host reaction (GVHR) that occurred in the LEW-to-F 1 rats was markedly reduced after the administration of FTY 720. FTY 720 combined with a low dose of CyA completely abrogated GVHR without any adverse reaction. FTY 720 treatment resulted in a significant decrease in the number of lymphocytes in the peripheral blood and the spleen, but the number of peripheral neutrophils was unchanged. Thus, FTY 720 would appear to be an ideal drug to combine with CyA in order to control the immune reaction after SBT.
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  • 117
    ISSN: 1432-0878
    Keywords: Key words: Oxytocin ; Immunocytochemistry ; Paraventricular nucleus ; Superior cervical ganglion ; Spinal cord ; Sympathetic nervous system ; Retrograde tracing ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. The paraventricular nucleus of the hypothalamus is a major integrative nucleus for relaying information from the suprachiasmatic nucleus to the autonomic system. The precise pathway by which this information can influence autonomic functions, such as melatonin synthesis in the pineal gland, is not clear. In the present study, we used a retrograde tracer injected in the superior cervical ganglion to identify spinal preganglionic neurons. One of the main neurotransmitters present in descending projections of the paraventricular nucleus of the hypothalamus, oxytocin, was detected with immunocytochemistry to visualise possible contacts with the neurons located in the intermediolateral column of the spinal cord and projecting to the superior cervical ganglion. Although many appositions could be seen at the light-microscopic level, this abundance could not be confirmed at the electron-microscopic level. The implications of these observations for the overall timing message received by the spinal preganglionic neurons are discussed.
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  • 118
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    European journal of plastic surgery 20 (1997), S. 136-140 
    ISSN: 1435-0130
    Keywords: Burn injury ; Stress protein ; HSP72 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to understand the stress response of systemic organs to severe burn injury, the induction of 72-kD heat shock protein (HSP72) in various organs (brain, hypophysis, lung, heart, liver, pancreas, spleen, kidney, adrenal gland, and skeletal muscle) was investigated in rats with severe burns. A full-thickness burn was induced on the rats' skin by immersing the rats in hot water (90° C) for 3 s. At 0, 24, and 48 h after the burn injury, the HSP72 expression of various organs was examined using the Western blot analysis. At 24 h after the burn injury, the level of HSP72 had increased in the hypophysis, lung, heart, and kidney. In all organs examined, the expression of HSP72 had increased at 48 h after the burn injury. The level of HSP72 was highest in the hypophysis (3.3-fold compared to the control), and lowest in the brain and adrenal gland (1.7-fold of the control) at 48 h after the burn injury. These results confirm that severe burn injury causes a stress response in systemic organs.
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  • 119
    ISSN: 1573-6903
    Keywords: Rat ; early development ; cerebral cortex ; hippocampus ; homocysteine seizures ; glutamate binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Specific [3H]glutamate binding to synaptic membranes from the cerebral cortex and hippocampus of 7-, 12- and 18-day-old rats was examined, both in control animals and during seizures induced by homocysteine. In the cerebral cortex a transient peak of glutamate binding was observed in 7-day-old group, whereas in the hippocampus it occurred in 12-day-old animals. Total specific [3H]glutamate binding was not influenced by preceding seizure activity in either of the age groups and both the studied regions. NMDA- and QA-sensitive glutamate bindings represent the highest portion of the total binding. Moreover, NMDA-sensitive binding in the cerebral cortex of 7-day-old rats is significantly higher as compared to the two more mature groups. The proportion of individual receptor subtypes on total binding in each age group was not influenced by preceding seizure activity. However, NMDA-sensitive binding in the hippocampus of 12-day-old rats, sacrificed during homocysteine-induced seizures, was significantly increased as compared to corresponding controls. In contrast to the effect of NMDA, AMPA, kainate and quisqualate which displaced to a different extent [3H]glutamate binding, homocysteine had no effect when added to membrane preparations. Similarly, [3H]CPP and [3H]AMPA bindings were not affected in the presence of homocysteine. It thus seems unlikely that homocysteine is an effective agonist for conventional ionotropic glutamate receptors. Its potential activity at some of the modulatory sites at the NMDA receptor channel complex or at metabotropic receptors has to be clarified in further experiments.
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  • 120
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    Langenbeck's archives of surgery 382 (1997), S. 33-36 
    ISSN: 1435-2451
    Keywords: Key words Fibrin ; Fibrinolysis ; Peritoneum ; Adhesions ; Rat ; Schlüsselwörter Fibrin ; Fibrinolyse ; Peritoneum ; Adhäsionen ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung In einem Rattenmodell wurde die Beeinflussung der Adhäsionsentstehung nach Laparotomien durch intraperitoneale Applikation verschiedener Fibrinolytika untersucht. Streptokinase und TPA verminderten die sero-serosale Haftung signifikant, nicht aber Urokinase. Die intravasale Gerinnung blieb unbeeinflußt.
    Notes: Abstract In a rat model, the effect of the intraperitoneal application of fibrinolytic agents on the development of adhesions was examined. Streptokinase and TPA reduced sero-serosal adhesions significantly, whereas urokinase did not reduce them. Intravascural coagulation was not affected.
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    Basic research in cardiology 92 (1997), S. 123-128 
    ISSN: 1435-1803
    Keywords: Rat ; ventricular myocyte ; action potential duration ; transient outward current ; 4-aminopyridine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rate-dependent alterations of action potential duration (APD) in rat ventricular myocytes were investigated. Action potentials of the isolated myocytes were recorded with patch electrodes containing EGTA (11 mM), and showed a marked rate-dependent prolongation in the APD (0.2–5 Hz). This prolongation was significantly inhibited in the presence of 4-aminopyridine (4-AP), a blocker of the transient outward K+ current (Ito). Thus, the rate-dependent decrease in Ito may underlie the change in APD. In contrast, the action potentials recorded from rat ventricular papillary muscles with conventional microelectrodes did not show rate-dependent alterations in the APD, i.e., the APD remained practically unaltered at the frequency range of 0.2–5 Hz. These results suggest that the rate-dependent prolongation of APD (due to rate-dependent blockade of Ito) becomes evident when the intracellular Ca2+ was chelated by the internal application of EGTA via patch pipette. We speculate that the rate-dependent prolongation of APD (via decreases in Ito) is masked in the ventricular papillary muscles, probably due to rate-dependent decreases in the inward current (e.g., electrogenic Na+−Ca2+ exchange current) that is regulated by the intracellular calcium.
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    Basic research in cardiology 92 (1997), S. 1-10 
    ISSN: 1435-1803
    Keywords: Rat ; rabbit ; ferret ; shortening ; fluorescence ; cardiac myocyte ; sarcoplasmic reticulum ; cardiac hypertrophy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract During relaxation of cardiac muscle four Ca transport systems can compete to remove Ca from the myoplasm. These are 1) the SR Ca-ATPase, 2) the sarcolemmal Na/Ca exchange, 3) the sarcolemmal Ca-ATPase, and 4) the mitochondrial Ca uniporter. Isolated ventricular myocytes loaded with the intracellular fluorescent Ca indicator indo-1 were used to study [Ca]i decline during relaxation. By selective inhibition of the various Ca transporters above the dynamic interaction of these systems during relaxation was evaluated. Quantitatively the SR Ca-ATPase and Na/Ca exchange are clearly the most important (accounting for 〉95% of Ca removal). However, the balance of Ca fluxes between these systems vary in a species dependent manner. For example, the SR is much more strongly dominant in rat ventricular myocytes, where ∼92% of Ca removal is via SR Ca-ATPase and only 7% via Na/Ca exchange during a twitch. In other species (rabbit, ferret, cat, and guinea-pig) the balance is more in the range of 70–75% SR Ca-ATPase and 25–30% Na/Ca exchange. Ferret ventricular myocytes also exhibit a unusually strong sarcolemmal Ca-ATPase. During the normal steady state cardiac contraction-relaxation cycle the same amount of Ca must leave the cell as enters over a cardiac cycle. This implies that 25–30% of the Ca required to activate contraction must enter the cell at each cardiac cycle. Experiments using voltage clamp to measure both Ca current and Na/Ca exchange current demonstrate that this amount of Ca may be supplied by the L-type Ca current. The ability of the SR Ca-ATPase to reduce [Ca]i may also be modified both acutely (e.g. by catecholamines) as well as chronically (e.g. during cardiac hypertrophy and heart failure). Using tissue cultured neonatal rat ventricular myocytes, we studied the effect of chronic arrest or stimulation with phorbol esters (to stimulate protein kinase C). Verapamil-induced arrest increased the SR Ca-ATPase at the level of mRNA, protein expression and functional ability to lower [Ca]i in intact cells. Conversely, stimulation or protein kinase C reduced SR Ca-ATPase at all three of these levels.
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    European archives of oto-rhino-laryngology and head & neck 254 (1997), S. 115-119 
    ISSN: 1434-4726
    Keywords: External auditory canal ; External otitis ; Pathogenesis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract External otitis was produced in 12 Sprague-Dawley rats by mechanical stimulation through a plastic micropipette inserted into the right external auditory canal (EAC). The EAC was later evaluated regarding the color of the skin, swelling and the presence of fluid. Within 1 day all rats developed an external otitis that was characterized by a red, swollen ear canal containing an opalescent fluid. The tympanic membrane and middle ear cavity appeared to be normal. No healed EACs were seen within the initial 10 days of follow-up and 4 of 6 rats still exhibited external otitis at day 21. Light microscopy of biopsy specimens revealed pronounced edema of the dermis of the ear canal. Mast cells were more numerous in the early phase of the otitis present, although very few inflammatory cells were found in tissues despite the marked inflammatory reaction produced. Findings show that this animal model for external otitis can be used to investigate pathogenesis as well as to test various treatment strategies.
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    European archives of oto-rhino-laryngology and head & neck 254 (1997), S. S9 
    ISSN: 1434-4726
    Keywords: Capsaicin ; Rhinitis ; BPC 157 ; Mastocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Protection of BPC 157 on capsaicin-induced rhinitis was studied in Wistar rats for its effect on mastocyte infiltration, degranulation and inflammatory cell infiltration. Animals were pretreated with 10 μg/kg, 10 ng/kg or 2 ml saline i.p. and capsaicin (0.05 ml/nostril of 1750 nmol/l sol.) was applied intranasally. They were then euthanized at 1, 3 and 12 h after capsaicin provocation. Nasal mucosa was analyzed and scored for mastocyte infiltration, degranulation and inflammatory cell infiltration. BPC 157 pretreatment significantly prevented mastocyte infiltration at 1 h. Polymorphonuclear leukocyte infiltration was significantly reduced in rats pretreated with 10 μg/kg BPC 157. A dose-dependent effect of BPC 157 pretreatment was demonstrated only for polymorphonuclear leukocyte infiltration at 12 h.
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    European archives of oto-rhino-laryngology and head & neck 254 (1997), S. 425-429 
    ISSN: 1434-4726
    Keywords: Tympanic membrane ; Myringotomy ; Myringosclerosis ; Fenspiride ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Earlier studies have revealed a relationship between the development of myringosclerosis and oxygen-derived free radicals. The latter can be blocked by the anti-inflammatory drug fenspiride. The present study was undertaken to test the ability of fenspiride to prevent myringosclerosis from developing during healing of the tympanic membrane. Myringotomized rats were treated with either topical applications or intraperitoneal injections of fenspiride for 12 days, after which the tympanic membranes were examined by otomicroscopy and studied histologically by light microscopy. Topically applied fenspiride was found to inhibit the development of sclerotic lesions, whereas intraperitoneal injections were ineffective.
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  • 126
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    Biotechnology and Bioengineering 55 (1997), S. 252-260 
    ISSN: 0006-3592
    Keywords: lipase ; chemical modification ; stability ; esterification ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Semipurified lipase of Candida rugosa (CRSL) was subjected to chemical modification, and the activities of the modified lipase, in hydrolysis and esterification reactions, were examined. The esterification reactions were carried out in the absence and presence of isooctane. When the enzyme was modified with polyethylene glycol (PEG), two methodologies were studied. The activation of PEG with p-NO2-phenylchloroformate gives better biocatalysts than those obtained with cyanuric chloride-PEG. The chemical modification with PEG increases the stability of pure lipases in isooctane at 50°C (extreme conditions). The chemically modified enzymes are useful for biotransformations in organic solvents. In addition the nitration of tyrosines with tetranitromethane was also studied. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 252-260, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 565-570 
    ISSN: 0006-3592
    Keywords: hybridoma ; hypoosmotic stress ; specific antibody productivity ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: To investigate the response of hybridoma cells to hypoosmotic stress, S3H5/γ2bA2 and DB9G8 hybridomas were cultivated in the hypoosmolar medium [Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% serum] resulting from sodium chloride subtraction. Both hybridomas showed similar responses to hypoosmotic stress in regard to cell growth and antibody production. The cell growth and antibody production at 276 mOsm/kg were comparable to those at 329 mOsm/kg (standard DMEM). Both cells grew well at 219 mOsm/kg, though their growth and antibody production were slightly decreased. When the osmolality was further decreased to 168 mOsm/kg, the cell growth did not occur. When subjected to hyperosmotic stress, both cells displayed significantly enhanced specific antibody productivity (qAb). However, the cells subjected to hypoosmotic stress did not display enhanced qAb. Taken together, both hyperosmotic and hypoosmotic stresses depressed the growth of S3H5/γ2bA2 and DB9G8 hybridomas. However, their response to hypoosmotic stress in regard to qAb was different from that to hyperosmotic stress. © 1997 John Wiley & Sons, Inc. Biotechnol Biong 55: 565-570, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 547-555 
    ISSN: 0006-3592
    Keywords: ethanol ; cellulose ; hemicellulose ; endoglucanase ; cellulase ; lignocellulose ; biomass ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: This study demonstrates a new approach to reduce the amount of fungal cellulase required for the conversion of cellulose into ethanol. Escherichia coli KO11, a biocatalyst developed for the fermentation of hemicellulose syrups, was used to produce recombinant endoglucanase as a co-product with ethanol. Seven different bacterial genes were expressed from plasmids in KO11. All produced cell-associated endoglucanase activity. KO11(pLOI1620) containing Erwinia chrysanthemi celZ (EGZ) produced the highest activity, 3,200 IU endoglucanase/L fermentation broth (assayed at pH 5.2 and 35°C). Recombinant EGZ was solubilized from harvested cells by treatment with dilute sodium dodecyl sulfate (12.5 mg/ml, 10 min, 50°C) and tested in fermentation experiments with commercial fungal cellulase (5 filter paper units/g cellulose) and purified cellulose (100 g/L). Using Klebsiella oxytoca P2 as the biocatalyst, fermentations supplemented with EGZ as a detergent-lysate of KO11(pLOI1620) produced 14%-24% more ethanol than control fermentations supplemented with a detergent-lysate of KO11(pUC18). These results demonstrate that recombinant bacterial endoglucanase can function with fungal cellulase to increase ethanol yield during the simultaneous saccharification and fermentation of cellulose. © 1997 Wiley & Sons, Inc. Biotechnol Bioeng 55: 547-555, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 577-580 
    ISSN: 0006-3592
    Keywords: mRNA stability ; hairpins ; gene expression control ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: An expression system has been developed for the introduction of DNA cassettes into the region between the transcription and translation start sites of a gene of interest. This cassette system was used to engineer mRNA stability through the introduction of hairpins at the 5′ end. A synthetic DNA cassette was designed so that the resulting mRNA hairpin would be positioned one nucleotide from the 5′ mRNA end. The hairpin-containing mRNA exhibited a half-life 3 times that of the mRNA with no hairpin, resulting in increases in both mRNA and protein levels. These results indicate that it is possible to engineer mRNA stability as an additional means of controlling gene expression. © 1997 John Wiley & Sons Inc. Biotechnol Bioeng 55: 557-580, 1997
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    Biotechnology and Bioengineering 55 (1997), S. 581-591 
    ISSN: 0006-3592
    Keywords: adsorptive membranes ; oscillatory flow ; integrated processes ; in situ product recovery ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Preferential transport in adsorptive membranes can be used to selectively remove biochemicals directly from fermentation broths. During preferential transport, an adsorbing solute is selectively transported across the membrane while nonadsorbing solutes and cells are retained by the membrane. This technique was used to separate lysozyme directly from a feed containing lysozyme, myoglobin, and yeast cells. We found that because the oscillatory flows used in preferential transport involve strokes that are close to symmetric, they are very efficient in alleviating cake formation due to cell deposition on the membrane surface. Theoretical results suggest that, by optimizing process variables, preferential transport can lead to a continuous concentrated stream of the adsorbing protein. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 54: 581-591, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 592-608 
    ISSN: 0006-3592
    Keywords: Saccharomyces cerevisiae ; metabolic modeling ; sensitivity analysis ; glycolysis ; compartmentation ; transient response ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: A mathematical model of glycolysis in Saccharomyces cerevisiae is presented. The model is based on rate equations for the individual reactions and aims to predict changes in the levels of intra- and extracellular metabolites after a glucose pulse, as described in part I of this study. Kinetic analysis focuses on a time scale of seconds, thereby neglecting biosynthesis of new enzymes. The model structure and experimental observations are related to the aerobic growth of the yeast. The model is based on material balance equations of the key metabolites in the extracellular environment, the cytoplasm and the mitochondria, and includes mechanistically based, experimentally matched rate equations for the individual enzymes. The model includes removal of metabolites from glycolysis and TCC for biosynthesis, and also compartmentation and translocation of adenine nucleotides. The model was verified by in vivo diagnosis of intracellular enzymes, which includes the decomposition of the network of reactions to reduce the number of parameters to be estimated simultaneously. Additionally, sensitivity analysis guarantees that only those parameters are estimated that contribute to systems trajectory with reasonable sensitivity. The model predictions and experimental observations agree reasonably well for most of the metabolites, except for pyruvate and adenine nucleotides. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 592-608, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 609-615 
    ISSN: 0006-3592
    Keywords: interacting populations ; membrane reactor ; induced metabolic changes ; elicitation ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The design of a reactor in which two interacting cell populations (microorganisms and plants) could grow under controlled conditions was considered. In this reactor, the cell populations are separated by a membrane which permits semi-in vivo study of induced interaction-specific changes in metabolism. In this paper, the interaction of suspension culture of Nicotiana tabacum (tobacco) and the Oomycete, Phytophthora nicotiana was simulated. The results of the computer simulation show the induced metabolic changes as a consequence of the biological interaction. The paper introduces a novel approach in the strategy for the study of interacting population in suspension cultures. This type of system has potential applications in studies of the regulation of secondary metabolism and for the production of high values pharmaceuticals. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 609-615, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 616-629 
    ISSN: 0006-3592
    Keywords: cell adhesion ; radial-flow chamber ; hydrodynamic shear ; detachment kinetics ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: The strength of adhesion and dynamics of detachment of murine 3T3 fibroblasts from self-assembled monolayers were measured in a radial-flow chamber (RFC) by applying models for fluid mechanics, adhesion strength probability distributions, and detachment kinetics. Four models for predicting fluid mechanics in a RFC were compared to evaluate the accuracy of each model and the significance of inlet effects. Analysis of these models indicated an outer region at large radial positions consistent with creeping flow, an intermediate region influenced by inertial dampening, and an inner region dominated by entrance effects from the axially-oriented inlet. In accompanying experiments patterns of the fraction of cells resisting detachment were constructed for individual surfaces as a function of the applied shear stress and evaluated by comparison with integrals of both a normal and a log-normal distribution function. The two functions were equally appropriate, yielding similar estimates of the mean strength of adhesion. Further, varying the Reynolds number in the inlet, Red, between 630 and 1480 (corresponding to volumetric flow rates between 0.9 and 2.1 mL/s) did not affect the mean strength of adhesion. For these same experiments, analysis of the dynamics of detachment revealed three temporal phases: 1) rapid detachment of cells at the onset of flow, consistent with a first-order homogeneous kinetic model; 2) time-dependent rate of detachment during the first 30 sec. of exposure to hydrodynamic shear, consistent with the first-order heterogeneous kinetic model proposed by Dickinson and Cooper (1995); and 3) negligible detachment, indicative of pseudo-steady state after 60 sec. of flow. Our results provide rigorous guidelines for the measurement of adhesive interactions between mammalian cells and prospective biomaterial surfaces using a RFC. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 616-629, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 693-700 
    ISSN: 0006-3592
    Keywords: glucose ; lactate ; real-time determination ; hematopoietic cell culture ; colony-forming cells ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Glucose and lactate metabolic rates were evaluated for cultures of cord blood (CB) mononuclear cell (MNC), peripheral blood (PB) MNC, and PB CD34+ cell cultures carried out in spinner flasks and in T-flasks in both serum-containing and serum-free media. Specific glucose uptake rates (qgluc, in micromoles per cell per hour) and lactate generation rates (qlac) correlated with the percentage of colony-forming cells (CFC) present in the culture for a broad range of culture conditions. Specifically, the time of maximum CFC percentage in each culture coincided with the time of maximum qgluc and qlac in cultures with different seeding densities and cytokine combinations. A two-population model (Qlac = α[CFC] + β([TC] - [CFC]), where [TC] is total cell concentration; Qlac is volumetric lactate production rate in micromoles per milliliter per hour; α is qlac for an average CFC; and β is qlac for an average non-CFC) was developed to describe lactate production. The model described lactate production well for cultures carried out in both T-flasks and spinner flasks and inoculated with either PB or CB MNC or PB CD34+ cells. The values for α and β that were derived from the model varied with both the inoculum density and the cytokine combination. However, preliminary results indicate that cultures carried out under the same conditions from different samples with similar initial CD34+ cell content have similar values for β and β. These findings suggest that it should be possible to use lactate production data to predict the harvest time that corresponds to the maximum number of CFC in culture. The ability to harvest ex vivo hematopoietic cultures for transplantation when CFC are at a maximum has the potential to speed the rate at which immunocompromised patients recover. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 693-700, 1997.
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  • 135
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    Keywords: tubular photobioreactors ; light distribution ; average solar irradiance ; light attenuation ; microalgae mass culture ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: A mathematical model to estimate the solar irradiance profile and average light intensity inside a tubular photobioreactor under outdoor conditions is proposed, requiring only geographic, geometric, and solar position parameters. First, the length of the path into the culture traveled by any direct or disperse ray of light was calculated as the function of three variables: day of year, solar hour, and geographic latitude. Then, the phenomenon of light attenuation by biomass was studied considering Lambert-Beer's law (only considering absorption) and the monodimensional model of Cornet et al. (1900) (considering absorption and scattering phenomena). Due to the existence of differential wavelength absorption, none of the literature models are useful for explaining light attenuation by the biomass. Therefore, an empirical hyperbolic expression is proposed. The equations to calculate light path length were substituted in the proposed hyperbolic expression, reproducing light intensity data obtained in the center of the loop tubes. The proposed model was also likely to estimate the irradiance accurately at any point inside the culture. Calculation of the local intensity was thus extended to the full culture volume in order to obtain the average irradiance, showing how the higher biomass productivities in a Phaeodactylum tricornutum UTEX 640 outdoor chemostat culture could be maintained by delaying light limitation. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 701-714, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 715-726 
    ISSN: 0006-3592
    Keywords: fungal morphology ; pellets ; hyphae ; hair of pellets ; agitation intensity ; fermentation ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Both parallel fermentations with Aspergillus awamori (CBS 115.52) and a literature study on several fungi have been carried out to determine a relation between fungal morphology and agitation intensity. The studied parameters include hyphal length, pellet size, surface structure or so-called hairy length of pellets, and dry mass per-wet-pellet volume at different specific energy dissipation rates. The literature data from different strains, different fermenters, and different cultivation conditions can be summarized to say that the main mean hyphal length is proportional to the specific energy dissipation rate according to a power function with an exponent of -0.25 ± 0.08. Fermentations with identical inocula showed that pellet size was also a function of the specific energy dissipation rate and proportional to the specific energy dissipation rate to an exponent of -0.16 ± 0.03. Based on the experimental observations, we propose the following mechanism of pellet damage during submerged cultivation in stirred fermenters. Interaction between mechanical forces and pellets results in the hyphal chip-off from the pellet outer zone instead of the breakup of pellets. By this mechanism, the extension of the hyphae or hair from pellets is restricted so that the size of pellets is related to the specific energy dissipation rate. Hyphae chipped off from pellets contribute free filamentous mycelia and reseed their growth. So the fraction of filamentous mycelial mass in the total biomass is related to the specific energy dissipation rate as well.To describe the surface morphology of pellets, the hyphal length in the outer zone of pellets or the so-called hairy length was measured in this study. A theoretical relation of the hairy length with the specific energy dissipation rate was derived. This relation matched the measured data well. It was found that the porosity of pellets showed an inverse relationship with the specific energy dissipation rate and that the dry biomass per-wet-pellet volume increased with the specific energy dissipation rates. This means that the tensile strength of pellets increased with the increase of specific energy dissipation rate. The assumption of a constant tensile strength, which is often used in literature, is then not valid for the derivation of the relation between pellet size and specific energy dissipation rate. The fraction of free filamentous mycelia in the total biomass appeared to be a function of the specific energy dissipation in stirred bioreactors. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 715-726, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 921-926 
    ISSN: 0006-3592
    Keywords: green fluorescent protein ; sensor ; on-line monitoring ; quantitation ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: We present an intensity based sensor designed for on-line monitoring of green fluorescent protein, a revolutionary marker of protein expression. The device consisted of a blue light emitting diode as the excitation source. A band pass excitation filter cut off light longer than 490 nm. The light was directed into a bifurcated optical fiber bundle with the common end inserted into a stainless steel housing equipped with a quartz window. The fiber bundle and stainless steel housing are steam sterilizable. The emission radiation was collected through a long wave pass filter to reject the excitation light shorter than 505 nm and was detected by a photomultiplier tube. The signal was amplified and sent to a computer for recording time course data. The sensor was tested in an Escherichia coli fermentation of JM105 transformed with pBAD-GFP. The on-line signal was compared to off-line fluorescence spectrophotometer measurements. The on-line profile closely followed the off-line. Western blot data showed that with a time shift, the sensor was able to both continuously and quantitatively monitor expression of green fluorescent protein on-line in real time. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55:921-926, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 909-920 
    ISSN: 0006-3592
    Keywords: baculovirus ; insect cells ; metabolism ; Sf-9; high five™ ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Nutrient utilization and byproduct accumulation were monitored in Spodoptera frugiperda Sf-9 and Trichoplusia ni BTI-Tn-5B1-4 (High Five™) cell lines during growth and following viral infection in suspension cultures in order to develop a better understanding of cell metabolism and to acquire information relevant to large scale fed-batch bioreactors. The utilization of glucose, dissolved oxygen, and amino acids were monitored in Sf-9 cell cultures grown in Sf-900 II serum-free medium (SFM) and in High Five™ cell cultures grown in both Sf-900 II and Express Five SFM. Using the optimal medium for each cell line, i.e., Sf-900 II SFM for Sf-9 cells and Express Five SFM for High Five™ cells, the cell growth rate, maximum cell density, specific glucose and glutamine utilization rates, and specific alanine production rate were comparable during cell growth. In addition, the expression level of recombinant human tissue plasminogen activator was comparable in the two cell lines on a per cell basis. It was found, however, that lactate and ammonia accumulated in High Five™ cell cultures, but not in Sf-9 cell cultures. In addition, High Five™ cells utilized asparagine more rapidly than glutamine, whereas Sf-9 cells consumed only minimal asparagine, and the oxygen utilization rate was significantly higher in High Five™ cell cultures. It was also found that the medium had a significant effect on High Five™ cell metabolism, e.g., the specific glucose utilization rate and the specific lactate and alanine production rates were significantly higher in Sf-900 II SFM than in Express Five SFM. In addition, the maximum cell density and specific asparagine utilization rate were significantly higher in Express Five SFM. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55:909-920, 1997.
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    Biotechnology and Bioengineering 55 (1997), S. 940-940 
    ISSN: 0006-3592
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: No abstract.
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  • 140
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    Biotechnology and Bioengineering 56 (1997), S. 1-8 
    ISSN: 0006-3592
    Keywords: transesterification ; hydrolysis ; water activity ; cutinase ; gas ; bioreactor ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Fusarium solani cutinase supported onto Chromosorb P was used to catalyze transesterification (alcoholysis) and hydrolysis on short volatile alcohols and esters in a continuous gas/solid bioreactor. In this system, a solid phase composed of a packed enzymatic preparation was continuously percolated with carrier gas which fed substrates and removed reaction products simultaneously. A kinetic study was performed under differential operating conditions in order to get initial reaction rates. The effect of the hydration state of the biocatalyst on the kinetics was studied for 3 conditions of hydration (aw = 0.2, aw = 0.4 and aw = 0.6), the alcoholysis of propionic acid methyl ester with n-propanol, and for 5 hydration levels (from aw = 0.2 to aw = 0.6) for the hydrolysis of propionic acid methyl, ethyl or propyl esters. F. solani cutinase was found to have an unusual kinetic behavior. A sigmoid relationship between the rate of transesterification and the activity of methyl propionate was observed, suggesting some form of cooperative activation of the enzyme by one of its substrate. For the hydrolysis of short volatile propionic acid alkyl esters, threshold effects on the reaction rate, highly depending on the water activity and the substrate polarity, are reported. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 56: 1-8, 1997.
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  • 141
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    Biotechnology and Bioengineering 56 (1997), S. 9-22 
    ISSN: 0006-3592
    Keywords: condensation reactions ; disaccharides ; equilibria ; glucoamylase ; kinetics ; monosaccharides ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Arabinose, fructose, galactose, myo-inositol, lyxose, mannose, ribose, and xylose were incubated individually and with glucose in the presence of Aspergillus niger glucoamylase at pH 4.5 and 45°C. Glucoamylase condenses galactose, glucose, and mannose individually into disaccharides. It also produces mixed disaccharides when each of the eight carbohydrates is incubated with glucose. Many products were identified by gas chromatography of the derivatized reaction mixtures followed by mass spectroscopy of the individual chromatographic peaks. Galacto-, gluco-, or mannopyranosyl rings appear to be present at the nonreducing ends of all the disaccharides produced. Molecules linked through primary hydroxyl groups have the highest equilibrium constants of all products formed, since these bonds are thermodynamically favored. However, glucoamylase is capable of forming bonds with many available hydroxyl groups, as previously demonstrated when it was incubated with glucose alone. Formation rates of different bonds linking different residues vary widely. These results demonstrate that glucoamylase has a wide selectivity toward residues it will condense into disaccharides and toward bonds it will form between them. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 56: 9-22, 1997.
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  • 142
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 134-139 
    ISSN: 0887-3585
    Keywords: CASP2 ; fold-recognition ; HMM ; structure library ; remote homology ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We discuss how methods based on hidden Markov models performed in the fold-recognition section of the CASP2 experiment. Hidden Markov models were built for a representative set of just over 1,000 structures from the Protein Data Bank (PDB). Each CASP2 target sequence was scored against this library of HMMs. In addition, an HMM was built for each of the target sequences and all of the sequences in PDB were scored against that target model, with a good score on both methods indicating a high probability that the target sequence is homologous to the structure. The method worked well in comparison to other methods used at CASP2 for targets of moderate difficulty, where the closest structure in PDB could be aligned to the target with at least 15% residue identity. Proteins, Suppl. 1:134-139, 1997. © 1998 Wiley-Liss, Inc.
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  • 143
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 172-178 
    ISSN: 0887-3585
    Keywords: protein folding ; force field ; molecular dynamics ; secondary structure ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Structure predictions for two targets from the CASP2 meeting are presented and compared with the experimental structure. These predictions were made using a novel simplified flexible geometry representation of protein structure. The method uses potentials which mimic the physical forces involved in protein folding in a simplified representation of protein structure, and not by directly using data derived from statistical analyses of known protein structures. Additionally, the method is designed to work with a single protein sequence. The method was successful in generating reasonable protein-like structures, with mainly buried hydrophobic residues, exposed charges, and a good fraction of secondary structure. Specific details of the structure were remarkably close to the experimental structure. However, the overall fold in both cases was totally wrong. Some specific causes of this incorrect folding are suggested and a major improvement to the algorithm proposed. Proteins, Suppl. 1:172-178, 1997. © 1998 Wiley-Liss, Inc.
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  • 144
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 198-204 
    ISSN: 0887-3585
    Keywords: protein-protein targets ; docking ; receptor binding site ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The docking section of CASP2 is reviewed. Seven small molecule ligand-protein targets and one protein-protein target were available for predictions. Many of the small molecule ligand complexes involved serine proteases. Overall results for the small molecule targets were good, with at least one prediction for each target being within 3 Å root-mean-square deviation (RMSD) for nearly all targets and within 2 Å RMSD for over half the targets. However, no single docking method seemed to consistently perform best. In addition, the predictions closest to the experimental results were not always those ranked the highest, pointing out that the evaluation (scoring) of potential solutions is still an area that needs improvement. The protein-protein target proved more difficult. None of the predictions did well in reproducing the geometry of the complex, although in many cases the interacting surfaces of the two proteins were predicted with reasonable accuracy. This target consisted of two large proteins and, therefore was a demanding target for docking methods. Proteins, Suppl. 1:198-204, 1997. © 1998 Wiley-Liss, Inc.
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  • 145
    ISSN: 0887-3585
    Keywords: molecular docking ; flexible docking ; protein-ligand interaction ; molecular flexibility ; conformational analysis ; drug design ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We have applied our docking program FLEXX to all eight CASP2 targets involving protein complexes with small ligands. Of the seven targets that were kept in the CASP2 experiment, we could solve two. We found important parts of the solution in four other examples, and were unsuccessful on the remaining example. This paper discusses all predictions in detail. Each of our prediction runs took just a few minutes of computer time on a standard workstation and could thus be demonstrated in real time at the CASP meeting. We believe that this speed is the prime strength of our program FLEXX. In quality, our predictions are competitive with those produced by other predictors. The experiment showed that possible objectives of improvement of the FLEXX program are to incorporate relevant aspects of receptor flexibility, deal with water molecules in the receptor pocket, allow for a postoptimization to refine favorable complexes, and improve the scoring function. Proteins, Suppl. 1:221-225, 1997. © 1998 Wiley-Liss, Inc.
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  • 146
    ISSN: 0887-3585
    Keywords: viral antigen ; epitope insertion ; recombinant protein ; x-ray structure ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We report the crystal structure of MalE-B133, a recombinant form of the maltodextrin-binding protein (MBP) of Escherichia coli carrying an inserted amino-acid sequence of a B-cell epitope from the preS2 region of the hepatitis B virus (HBV). The structure was determined by molecular replacement methods and refined to 2.7 Å resolution. MalE-B133 is an insertion/deletion mutant of MBP in which residues from positions 134 to 142, an external α helix in the wild-type structure, are replaced by a foreign peptide segment of 19 amino acids. The inserted residues correspond to the preS2 sequence from positions 132 to 145 and five flanking residues that arise from the creation of restriction sites. The conformation of the recombinant protein, excluding the inserted segment, closely resembles that of wild-type MBP in the closed maltose-bound form. MalE-B133 was shown by previous studies to display certain immunogenic and antigenic properties of the hepatitis B surface antigen (HBsAg), which contains the preS2 region. The crystal structure reveals the conformation of the first nine epitope residues (preS2 positions 132 to 140) exposed on the surface of the molecule. The remaining five epitope residues (preS2 positions 141 to 145) are not visible in electron density maps. The path of the polypeptide chain in the visible portion of the insert differs from that of the deleted segment in the structure of wild-type MBP, displaying a helical conformation at positions 134 to 140 (preS2 sequence numbering). A tripeptide (Asp-Pro-Arg) at the N terminus of the helix forms a stable structural motif that may be implicated in the cross-reactivity of anti-HBsAg antibodies with the hybrid protein. Proteins 27:1-8 © 1997 Wiley-Liss, Inc.
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  • 147
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 36-46 
    ISSN: 0887-3585
    Keywords: GOR ; neural networks ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We propose a binary word encoding to improve the protein secondary structure prediction. A binary word encoding encodes a local amino acid sequence to a binary word, which consists of 0 or 1. We use an encoding function to map an amino acid to 0 or 1. Using the binary word encoding, we can statistically extract the multiresidue information, which depends on more than one residue. We combine the binary word encoding with the GOR method, its modified version, which shows better accuracy, and the neural network method. The binary word encoding improves the accuracy of GOR by 2.8%. We obtain similar improvement when we combine this with the modified GOR method and the neural network method. When we use multiple sequence alignment data, the binary word encoding similarly improves the accuracy. The accuracy of our best combined method is 68.2%. In this paper, we only show improvement of the GOR and neural network method, we cannot say that the encoding improves the other methods. But the improvement by the encoding suggests that the multiresidue interaction affects the formation of secondary structure. In addition, we find that the optimal encoding function obtained by the simulated annealing method relates to non-polarity. This means that nonpolarity is important to the multiresidue interaction. Proteins 27:36-46 © 1997 Wiley-Liss, Inc.
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  • 148
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 59-70 
    ISSN: 0887-3585
    Keywords: comparative protein modeling ; sequence similarity ; sequence-structure compatibility ; model quality ; CD40 receptor-ligand interactions ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The interaction between the human B cell receptor CD40 and its ligand on T cells is critical for B cell proliferation and the regulation of humoral immune responses. CD40 is a member of the tumor necrosis factor receptor (TNFR) family. We report here the construction and analysis of a detailed three-dimensional model of the TNFR-homologous extracellular region of CD40. This study provides an example for structure-based model building in the presence of low sequence similarity. The assessment of model quality and sequence-structure compatibility is emphasized, and limitations of the model are discussed. The current CD40 model predicts structural details beyond the backbone level. Features of the CD40 ligand binding site are discussed in conjunction with the results of a previous mutagenesis study. Proteins 27:59-70 © 1997 Wiley-Liss, Inc.
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  • 149
    ISSN: 0887-3585
    Keywords: thermophilic β-glycosidase ; protein conformational dynamics ; frequency domain fluorometry ; circular dichroism ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The conformational dynamics of β-glycosidase from Sulfolobus solfataricus was investigated by following the emission decay arising from the large number of tryptophanyl residues that are homogeneously dispersed in the primary structure. The fluorescence emission is characterized by a bimodal lifetime distribution, suggesting that the enzyme structure contains rigid and flexible regions, properly located in the macromolecule. The enzyme activity and thermostability appear to be related to the dynamic properties of these regions as evidenced by perturbation studies of the enzyme structure at alkaline pH and by addition of detergents such as SDS. The pH increase affects the protein dynamics with a remarkable loss of thermal stability and activity; these changes occur without any significant variation in the secondary structure as revealed by far-UV dichroic measurements. In the presence of 0.02% (w/v) SDS at alkaline pH, the enzymatic activity and thermostability are recovered. Under these conditions, the conformational dynamics appear to be similar to that evidenced at neutral pH. Further increases in SDS concentration, at alkaline pH, render the activity and thermostability of β-glycosidase similar to those observed in the absence of detergent. Proteins 27:71-79 © 1997 Wiley-Liss, Inc.
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  • 150
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 118-130 
    ISSN: 0887-3585
    Keywords: homology modeling ; glutathione transferases ; theta class GSTs ; glutathione ; menaphthyl sulfate ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A tertiary model of the human GSTT2 Theta class glutathione transferase is presented based on the recently solved crystal structure of a related thetalike isoenzyme from Lucilia cuprina. Although the N-terminal domains are quite homologous, the C-terminal domains share less than about 20% identity. The model is used to consolidate the role of Ser 11 in the active site of the enzyme as well as to identify other residues and mechanisms of likely catalytic importance. The T2 subfamily of theta class enzymes have been shown to inactivate reactive sulfate esters arising from arylmethanols. A possible reaction pathway involving the conjugation of glutathione with one such sulfate ester, 1-menaphthyl-sulfate, is described. It is also proposed that the C-terminal region of the enzyme plays an important role in allowing substrate access to the active site. Proteins 27:118-130 © 1997 Wiley-Liss, Inc.
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  • 151
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 96-109 
    ISSN: 0887-3585
    Keywords: IL-6/IL-6R complex ; gp130 ; cytokines ; model building ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The cytokines IL-6, LIF, CNTF, OSM, IL-11, and CT-1 have been grouped into the family of IL-6-type cytokines, since they all require gp130 for signal transduction. Interestingly, gp130 binds directly to OSM, whereas complex formation with the other cytokines depends on additional receptor subunits. Only limited structural information on these cytokines and their receptors is available. X-ray structures have been solved for the cytokines LIF and CNTF, whose up-up-down-down four-helix bundle is common to all of these cytokines, and for the receptors of hGH and prolactin, which contain two domains with a fibronectin III-like fold. Since cocrystallization and x-ray analysis of the up to four different proteins forming the receptor complexes of the IL-6-type cytokines is unlikely to be achieved in the near future, model building based on the existing structural information is the only approach for the time being. Here we present model structures of the complexes of human and murine IL-6 with their receptors. Their validity can be deduced from the fact that published mutagenesis data and the different receptor specificity of human and murine IL-6 can be understood. It is now possible to predict the relative positions and contacts for all molecules in their respective complexes. Such information can be used for the rational design of cytokine and receptor antagonists, which may have a valuable therapeutic perspective. Proteins 27:96-109 © 1997 Wiley-Liss, Inc.
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  • 152
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 131-143 
    ISSN: 0887-3585
    Keywords: protein structure ; protein dynamics ; molecular mechanics ; NOE ; NMR ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Acyl carrier proteins (ACPs) from spinach and from Escherichia coli have been used to demonstrate the utility of proton NMR for comparison of homologous structures. The structure of E. coli ACP had been previously determined and modeled as a rapid equilibrium among multiple conformational forms (Kim and Prestegard, Biochemistry 28:8792-8797, 1989). Spinach ACP showed two slowly exchanging forms and could be manipulated into one form for structural study. Here we compare this single form to postulated multiple forms of E. coli ACP using the limited amount of NOE data available for the spinach protein. A number of long-range NOE contacts were present between homologous residues in both spinach and E. coli ACP, suggesting tertiary structural homology. To allow a more definitive structural comparison, a method was developed to use spinach ACP NOE constraints to search for regions of structural divergence from two postulated forms of E. coli ACP. The homologous regions of the two protein sequences were aligned, additional distance constraints were extracted from the E. coli structure, and these were mapped onto the spinach sequence. These distance constraints were combined with experimental NOE constraints and a distance geometry simulated annealing protocol was used to test for compatibility of the constraints. All of the experimental spinach NOE constraints could be successfully combined with the E. coli data, confirming the general hypothesis of structural homology. A better fit was obtained with one form, suggesting a preferential stabilization of that form in the spinach case. Proteins 27:131-143 © 1997 Wiley-Liss, Inc.
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  • 153
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 144-153 
    ISSN: 0887-3585
    Keywords: calcium ; plant ; environmental stress ; TCH genes ; signal transduction ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Plants adapt to various stresses by developmental alterations that render them less easily damaged. Expression of the TCH2 gene of Arabidopsis is strongly induced by stimuli such as touch and wind. The gene product, TCH2, belongs to the calmodulin (CaM) family of proteins and contains four highly conserved Ca2+-binding EF-hands. We describe here the structure of TCH2 in the fully Ca2+-saturated form, constructed using comparative molecular modeling, based on the x-ray structure of paramecium CaM. Like known CaMs, the overall structure consists of two globular domains separated by a linker helix. However, the linker region has added flexibility due to the presence of 5 glycines within a span of 6 residues. In addition, TCH2 is enriched in Lys and Arg residues relative to other CaMs, suggesting a preference for targets which are more negatively charged. Finally, a pair of Cys residues in the C-terminal domain, Cys126 and Cys131, are sufficiently close in space to form a disulfide bridge. These predictions serve to direct future biochemical and structural studies with the overall aim of understanding the role of TCH2 in the cellular response of Arabidopsis to environmental stimuli. Proteins 27:144-153 © 1997 Wiley-Liss, Inc.
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  • 154
    ISSN: 0887-3585
    Keywords: tetrahydrofolate ; protein crystallization ; folate coenzymes ; purine synthesis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A bifunctional enzyme that catalyzes the conversion of formyltetrahydrofolate to methylene-tetrahydrofolate (5,10-methenyltetrahydrofolate cyclohydrolase and 5,10-methylene tetrahydrofolate dehydrogenease), has been subcloned from a cDNA library, purified to homogeneity, and crystallized. The crystals belong to space group I222, with unit cell dimensions of a= 64.5 Å b= 84.9 Å c= 146.1 Å. The crystal unit cell and diffraction is consistent with an asymmetric unit consisting of the enzyme monomer, and a specific volume of the unit cell of 3.2 Å3/Da. The crystals diffract to at least 2.8 Å resolution after flash-cooling, when using a rotating anode x-ray source and an RAXIS image plate detector. A 2.56 Å resolution native data set has been collected at beamline X12-C at the NSLS. © 1997 Wiley-Liss, Inc.
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  • 155
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 272-278 
    ISSN: 0887-3585
    Keywords: anion hydrolysis ; CA inhibitors ; substrates/inhibitors adducts ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A study was undertaken to investigate whether diverse carbonic anhydrase (CA) isozymes (both native Zn as well as cobalt-substituted) are able to catalyze the hydrolysis of anions such as cyanide, cyanate, and thiocyanate. A controversy exists between the crystallographic and spectroscopic data of CA II-anion adducts. In the former case it has been shown that “metal poisons” such as CN-and CNO-are not directly coordinated to the active site Zn(II) ion whereas spectroscopic studies indicate otherwise. A theoretical study in the above systems did not resolve this controversy, since it was calculated that all three anions can act as CA substrates. In this paper we prove experimentally that none of them may act as substrates of CA and propose an explanation to the above controversy, discussing the mode of binding of small molecules within the enzyme active site. © 1997 Wiley-Liss, Inc.
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  • 156
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 360-366 
    ISSN: 0887-3585
    Keywords: disulfide bond ; extracellular protein ; intracellular protein ; short-, medium-, and long-range interactions ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The free energy difference between folded and unfolded state is about the same for most proteins and it is not more than the energy of a few noncovalent interactions. In addition to the numerous noncovalent interactions, some proteins contain one or more disulfide bonds, which, as covalent crosslinks, significantly stabilize their tertiary structure. Correlation between the presence of disulfide bond(s), and the number noncovalent interresidue interactions of various kinds is analyzed here. The number of interactions per residue is almost the same for all protein. Also the number of long-range interactions per residue is the same in all proteins. Proteins with S(SINGLE BOND)S bond(s) (extracellular proteins) have more medium-range and fewer short-range interactions than those without S(SINGLE BOND)S bonds. However, the difference is independent of the number of these covalent crosslinks. We concluded that the different distributions of the various kinds of noncovalent interaction reflect the needs of proteins in the different environments, the extracellular and the intracellular ones, rather than the presence of the disulfide bond(s). We also pointed out that the observed differences in the distributions of short- and medium-range interactions are in good agreement with different secondary structure compositions of extracellular and intracellular proteins. Proteins 27:360-366, 1997. © 1997 Wiley-Liss, Inc.
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  • 157
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 336-344 
    ISSN: 0887-3585
    Keywords: hydrophobicity ; molecular evolution ; local propensities ; reverse hydrophobic effect ; protein stability ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: To investigate how the properties of individual amino acids result in proteins with particular structures and functions, we have examined the correlations between previously derived structure-dependent mutation rates and changes in various physical-chemical properties of the amino acids such as volume, charge, α-helical and β-sheet propensity, and hydrophobicity. In most cases we found the ΔG of transfer from octanol to water to be the best model for evolutionary constraints, in contrast to the much weaker correlation with the ΔG of transfer from cyclohexane to water, a property found to be highly correlated to changes in stability in site-directed mutagenesis studies. This suggests that natural evolution may follow different rules than those suggested by results obtained in the laboratory. A high degree of conservation of a surface residue's relative hydrophobicity was also observed, a fact that cannot be explained by constraints on protein stability but that may reflect the consequences of the reverse-hydrophobic effect. Local propensity, especially α-helical propensity, is rather poorly conserved during evolution, indicating that non-local interactions dominate protein structure formation. We found that changes in volume were important in specific cases, most significantly in transitions among the hydrophobic residues in buried locations. To demonstrate how these techniques could be used to understand particular protein families, we derived and analyzed mutation matrices for the hypervariable and framework regions of antibody light chain V regions. We found a surprisingly high conservation of hydrophobicity in the hypervariable region, possibly indicating an important role for hydrophobicity in antigen recognition. Proteins 27:336-344, 1997. © 1997 Wiley-Liss, Inc.
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  • 158
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 345-359 
    ISSN: 0887-3585
    Keywords: alphavirus structure ; Semliki Forest virus capsid protein ; autocatalysis ; capsid assembly ; conformational changes ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Alphaviruses are enveloped, insect-borne viruses, which contain a positive-sense RNA genome. The protein capsid is surrounded by a lipid membrane, which is penetrated by glycoprotein spikes. The structure of the Sindbis virus (SINV) (the type virus) core protein (SCP) was previously determined and found to have a chymotrypsin-like structure. SCP is a serine proteinase which cleaves itself from a polyprotein. Semliki Forest virus (SFV) is among the most distantly related alphaviruses to SINV. Similar to SCP, autocatalysis is inhibited in SFCP after cleavage of the polyprotein by leaving the carboxy-terminal tryptophan in the specificity pocket. The structures of two different crystal forms (I and II) of SFV core protein (SFCP) have been determined to 3.0 Å and 3.3 Å resolution, respectively. The SFCP monomer backbone structure is very similar to that of SCP. The dimeric association between monomers, A and B, found in two different crystal forms of SCP is also present in both crystal forms of SFCP. However, a third monomer, C, occurs in SFCP crystal form I. While monomers A and B make a tail-to-tail dimer contact, monomers B and C make a head-to-head dimer contact. A hydrophobic pocket on the surface of the capsid protein, the proposed site of binding of the E2 glycoprotein, has large conformational differences with respect to SCP and, in contrast to SCP, is found devoid of bound peptide. In particular, Tyr184 is pointing out of the hydrophobic pocket in SFCP, whereas the equivalent tyrosine in SCP is pointing into the pocket. The conformation of Tyr184, found in SFCP, is consistent with its availability for iodination, as observed in the homologous SINV cores. This suggests, by comparison with SCP, that E2 binding to cores causes major conformational changes, including the burial of Tyr184, which would stabilize the intact virus on budding from an infected cell. The head-to-tail contacts found in the pentameric and hexameric associations within the virion utilize the same monomer surface regions as found in the crystalline dimer interfaces. Proteins 27:345-359, 1997. © 1997 Wiley-Liss, Inc.
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  • 159
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 469-469 
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: No abstract.
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  • 160
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 471-480 
    ISSN: 0887-3585
    Keywords: protein hydration ; potentials-of-mean-force ; hydrophilic hydration ; hydrophobic hydration ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We present a statistical mechanical description of biomolecular hydration that accurately describes the hydrophobic and hydrophilic hydration of a model α-helical peptide. The local density of water molecules around a biomolecule is obtained by means of a potential-of-mean-force (PMF) expansion in terms of pair- and triplet-correlation functions of bulk water and dilute solutions of nonpolar atoms. The accuracy of the method is verified by comparing PMF results with the local density and site-site correlation functions obtained by molecular dynamics simulations of a model α-helix in solution. The PMF approach quantitatively reproduces all features of the peptide hydration determined from the molecular dynamics simulation. Regions of hydrophobic hydration near the Cα and Cβ atoms along the helix are well reproduced. The hydration of exposed polar groups at the N- and C-termini of the helix are also well described by the theory. A detailed comparison of the local hydration by means of site-site radial distribution functions evaluated with the PMF theory shows agreement with the molecular dynamics simulations. The formulation of this theory is general and can be applied to any biomolecular system. The accuracy, speed of computation, and local character of this theory make it especially suitable for studying large biomolecular systems. © 1997 Wiley-Liss Inc.
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  • 161
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 507-516 
    ISSN: 0887-3585
    Keywords: insulin ; despentapeptide ; structure ; fibrillation ; x-ray crystallography ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The crystal structure of despentapeptide insulin, a monomeric insulin, has been refined at 1.3 Å spacing and subsequently used to predict and model the organization in the insulin fibril. The model makes use of the contacts in the densely packed despentapeptide insulin crystal, and takes into account other experimental evidence, including binding studies with Congo red. The dimensions of this model fibril correspond well with those measured experimentally, and the monomer-monomer contacts within the fibril are in accordance with the known physical chemistry of insulin fibrils. Using this model, it may be possible to predict mutations in insulin that might alleviate problems associated with fibril formation during insulin therapy. © 1997 Wiley-Liss Inc.
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  • 162
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 517-522 
    ISSN: 0887-3585
    Keywords: Bacillus subtilis ; ferrochelatase ; hemH ; protein structure prediction ; α/β barrel ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: An α/β barrel is predicted for the three-dimensional (3D) structure of Bacillus subtilis ferrochelatase. To arrive at this structure, the THREADER program was used to find possible homologous 3D structures and to predict the secondary structure for the ferrochelatase sequence. The secondary structure was fit by hand to the selected homologous 3D structure then the MODELLER program was used to predict the fold of ferrochelatase. Molecular biological information about the conserved residues of ferrochelatase was used as the criteria to help select the homologous 3D structure used to predict the fold of ferrochelatase. Based on the predicted structure possible, ligands binding to the iron and protoporphyrin IX are discussed. The structure has been deposited in the Brookhaven database as ID 1FJI. © 1997 Wiley-Liss Inc.
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  • 163
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 556-566 
    ISSN: 0887-3585
    Keywords: protein minimization ; protein engineering ; disulfide mutant ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The characteristic CXC chemokine disulfide core of interleukin-8 (IL-8) has been rearranged in a variant replacing the 9 - 50 disulfide with a 9 - 38 disulfide. The new variant has been characterized by its binding affinity to IL-8 receptors A and B and the erythrocyte receptor DARC. This variant binds the three receptors with affinities between 500- and 2,500-fold lower than wild-type IL-8. Binding affinity results are also reported for the variant with alanine substituted for both cysteines 9 and 50. The Glu38 → Cys/Cys50 → Ala IL-8 crystallizes in space group P212121 with cell parameters a = 46.4, b = 49.2, and c = 69.5 Å, and has been refined to an R-value of 19.4% for data from 10 to 2 Å resolution. Analysis of the structure confirms the new disulfide arrangement and suggests that changes at Ile10 may be the principal cause of the lowered affinities. © 1997 Wiley-Liss Inc.
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  • 164
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    Proteins: Structure, Function, and Genetics 28 (1997), S. 375-379 
    ISSN: 0887-3585
    Keywords: protease II ; prohormone convertase ; paired basic amino acid cleaving enzyme ; ionic strength ; substrate inhibition ; rate-limiting step ; kinetic deuterium isotope effect ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Basic amino acid pairs in polypeptides represent important markers for processing enzymes to produce biologically active products. Such enzymes related to the serine peptidase subtilisin have recently been identified in eukaryotes. Herein is described and kinetically characterized a new type of processing enzyme, oligopeptidase B, which is encountered in the prokaryote Escherichia coli, and belongs to the prolyl oligopeptidase family of serine peptidases. The enzyme hydrolyzes the peptides at the carboxy end of dibasic sites by two orders of magnitude faster with respect to monobasic substrates. The kcat/Km is extremely high, 63 μM-1 s-1, for the substrate benzyloxycarbonyl-L-arginyl-L-arginyl-7-(4- methylcoumaryl)amide. The bell-shaped pH dependence of the rate constant is perturbed by some ionizing group(s). This effect is abolished at 1 M NaCl. In addition, high ionic strength inhibits the reaction considerably by increasing Km, which is indicative of an electrostatic interaction between the arginyl residues and the enzymatic carboxy groups. In distinction from that found with most serine endopeptidases, kinetic deuterium isotope measurements with oligopeptidase B indicate that the rate-limiting step of the reaction is a physical step rather than a chemical one characterized by general acid/base catalysis. The present result will contribute to our understanding of the processing phenomena in prokaryotes, as well as in higher organisms. Proteins 28:375-379, 1997. © 1997 Wiley-Liss, Inc.
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  • 165
    ISSN: 0887-3585
    Keywords: protein folding ; denatured states ; fast diffusive motions ; internal dynamics ; phosphoglycerate kinase ; incoherent quasielastic neutron scattering ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Quasielastic neutron scattering experiments performed on yeast phosphoglycerate kinase in the native form and denatured in 1.5 M guanidinium chloride reveal a change in the fast (picosecond time scale) diffusive internal dynamics of the protein. The momentum and energy transfer dependences of the scattering for both states are fitted by an analytical model in which, on the experimentally accessible picosecond time scale and angstrom length scale, the dynamics of a fraction of the nonexchangeable hydrogens in the protein is described as a superposition of vibrations with uniform diffusion in a sphere, the rest of the hydrogens undergoing only vibrational motion. The fraction diffusing changes, from ≈60% in the native protein to ≈82% in the denatured protein. The radius of the sphere also changes slightly, from ≈1.8 Å in the native protein to ≈2.2 Å in the denatured protein. Possible implications of these results for the general protein folding problem are discussed. Proteins 28:380-387, 1997 © 1997 Wiley-Liss, Inc.
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  • 166
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    Proteins: Structure, Function, and Genetics 28 (1997), S. 344-359 
    ISSN: 0887-3585
    Keywords: helix stabilizing/destabilizing interactions ; helix-capping motifs ; helical boundaries ; structure prediction ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A novel helix-coil transition theory has been developed. This new theory contains more types of interactions than similar theories developed earlier. The parameters of the models were obtained from a database of 351 nonhomologous proteins. No manual adjustment of the parameters was performed. The interaction parameters obtained in this manner were found to be physically meaningful, consistent with current understanding of helix stabilizing/destabilizing interactions. Novel insights into helix stabilizing/destabilizing interactions have also emerged from this analysis. The theory developed here worked well in sorting out helical residues from amino acid sequences. If the theory was forced to make prediction on every residue of a given amino acid sequence, its performance was the best among ten other secondary structural prediction algorithms in distinguishing helical residues from nonhelical ones. The theory worked even better if one only required it to make prediction on residues that were “predictable” (identifiable by the theory); 〉90% predictive reliability could be achieved. The helical residues or segments identified by the helix-coil transition theory can be used as secondary structural contraints to speed up the prediction of the three-dimensional structure of a protein by reducing the dimension of a computational protein folding problem. Possible further improvements of this helix-coil transition theory are also discussed. Proteins 28:344-359, 1997. © 1997 Wiley-Liss, Inc.
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  • 167
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    Proteins: Structure, Function, and Genetics 28 (1997), S. 388-404 
    ISSN: 0887-3585
    Keywords: homology modeling ; cytochrome P450 ; sequence alignment ; structure prediction ; maximal cliques ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A computational strategy for homology modeling, using several protein structures comparison, is described. This strategy implies a formalized definition of structural blocks common to several protein structures, a new program to compare these structures simultaneously, and the use of consensus matrices to improve sequence alignment between the structurally known and target proteins. Applying this method to cytochromes P450 led to the definition of 15 substructures common to P450cam, P450BM3, and P450terp, and to proposing a 3D model of P450eryF. Proteins 28:388-404, 1997 © 1997 Wiley-Liss, Inc.
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  • 168
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    Proteins: Structure, Function, and Genetics 28 (1997), S. 421-433 
    ISSN: 0887-3585
    Keywords: molecular recognition ; binding energy landscapes ; recognition nucleus ; structural harmony ; minimal frustration principle ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Computational structure prediction of streptavidin-peptide complexes for known recognition sequences and a number of random di-, tri-, and tetrapeptides has been conducted, and mechanisms of peptide recognition with streptavidin have been investigated by a new computational protocol. The structural consensus criterion, which is computed from multiple docking simulations and measures the accessibility of the dominant binding mode, identifies recognition motifs from a set of random peptide sequences, whereas energetic analysis is less discriminatory. The predicted conformations of recognition tripeptide and tetrapeptide sequences are also in structural harmony and composed of peptide fragments that are individually unfrustrated in their bound conformation, resulting in a minimally frustrated energy landscape for recognition peptides. Proteins 28:421-433, 1997. © 1997 Wiley-Liss, Inc.
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  • 169
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    Proteins: Structure, Function, and Genetics 28 (1997), S. 405-420 
    ISSN: 0887-3585
    Keywords: classification ; clustering ; protein domains ; genome annotation ; hidden Markov model ; Caenorhabditis elegans ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Databases of multiple sequence alignments are a valuable aid to protein sequence classification and analysis. One of the main challenges when constructing such a database is to simultaneously satisfy the conflicting demands of completeness on the one hand and quality of alignment and domain definitions on the other. The latter properties are best dealt with by manual approaches, whereas completeness in practice is only amenable to automatic methods. Herein we present a database based on hidden Markov model profiles (HMMs), which combines high quality and completeness. Our database, Pfam, consists of parts A and B. Pfam-A is curated and contains well-characterized protein domain families with high quality alignments, which are maintained by using manually checked seed alignments and HMMs to find and align all members. Pfam-B contains sequence families that were generated automatically by applying the Domainer algorithm to cluster and align the remaining protein sequences after removal of Pfam-A domains. By using Pfam, a large number of previously unannotated proteins from the Caenorhabditis elegans genome project were classified. We have also identified many novel family memberships in known proteins, including new kazal, Fibronectin type III, and response regulator receiver domains. Pfam-A families have permanent accession numbers and form a library of HMMs available for searching and automatic annotation of new protein sequences. Proteins: 28:405-420, 1997. © 1997 Wiley-Liss, Inc.
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  • 170
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    Proteins: Structure, Function, and Genetics 28 (1997), S. 452-453 
    ISSN: 0887-3585
    Keywords: crystallography ; F-actin crosslinker ; actin binding ; fimbrin ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We have crystallized the N-terminal actin binding domain (ABD1) of human fimbrin, a representative member of the largest class of actin crosslinking proteins. Diffraction from these crystals is consistent with the orthorhombic space group P212121 (a = 50.03 Å, b = 61.24 Å, c = 102.30 Å). These crystals contain one molecule in the asymmetric unit and diffract to at least 1.9 Å resolution. The crystal structure of ABD1 will be the first structure of an actin crosslinking domain. Proteins 28:452-453, 1997. © 1997 Wiley-Liss, Inc.
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  • 171
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    Keywords: molecular dynamics ; TMD algorithm ; GROMOS ; oncogenes ; G-proteins ; molecular switch ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The transitions between the water-equilibrated structures of the GTP and GDP forms of Ha-ras-p21 have been calculated by using the targeted molecular dynamics (TMD) method (Schlitter et al., Mol. Sim. 10:291-309, 1993) both in vacuo and with explicit solvent simulation. These constrained molecular dynamics calculations result in different pathways, depending on the nucleotide bound. Each pathway consists in a sequence of transitions affecting six segments of the protein, four of them forming a hydrophilic cleft around the nucleotide. The transitions are initiated by the removal or introduction of the γ-phosphate of the nucleotide and proceed sequentially, crossing several low-energy transition states. The movements are transmitted either by direct interactions between the segments or through the nucleotide. The GTP to GDP pathway is initiated by the removal of the nucleotide γ-phosphate. This gives some space to Gly12, Gly13, and Val14. Their movement is transmitted to the target recognition domain and the switch II region, forcing these segments to adopt another position. In a second step the target recognition domain and the switch II region undergo conformational transitions to reach an intermediate conformation. Finally, there is a relaxation of the target recognition domain to its final state that forces the switch II region to reach its target conformation. The calculated pathways allow the identification of many residues that play an important role in the conformational changes, explain the altered transformation properties of some, and suggest mutations to alter the pathway. Proteins 28:434-451, 1997. © 1997 Wiley-Liss, Inc.
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  • 172
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 167-171 
    ISSN: 0887-3585
    Keywords: sequence profiles building-blocks ; secondary helix ; strand turn knowledge-based ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Blind predictions of the local structure of nine CASP2 targets were made using the I-sites library of short sequence - structure motifs, revealing strengths and weaknesses in this new knowledge-based method. Many turns between secondary structural elements were accurately predicted. Estimates of the confidence of prediction correlated well with the accuracy over the whole set. Bias toward structures used to develop the library was minimal, probably because of the extensive use of cross-validation. However, helix positions were better predicted by the PHD program. The method is likely to be sensitive to the quality of the sequence alignment. A general measure for evaluating local structure predictions is suggested. Proteins, Suppl. 1:167-171, 1997. © 1998 Wiley-Liss, Inc.
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  • 173
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 492-507 
    ISSN: 0887-3585
    Keywords: folding intermediates ; NMR ; protein folding ; dimethylsulfoxide ; near-UV circular dichroism ; lysozyme ; molten globules ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A partly folded state of hen egg-white lysozyme has been characterized in 50% DMSO. Low concentrations of DMSO (〈10%) have little effect on the overall folded conformation of lysozyme as seen from 1H NMR chemical shift dispersion. At increasing DMSO concentrations (〉10%) a cooperative transition of the structure to a new, partially folded state is observed. This transition is essentially complete by ∼50% DMSO. NMR studies show an overall decrease in chemical shift dispersion with marked broadening of many resonances. A substantial number of backbone and side chain-side chain NOEs suggests the presence of secondary and tertiary interactions in the intermediate state. Tertiary organization of the aromatic residues is also demonstrated by enhanced near-UV circular dichroism and limited exposure of tryptophans as monitored by iodide quenching of fluorescence. The intermediate state exhibits enhanced binding to hydrophobic dyes. Further, the structural transition from this state to a largely unfolded conformation is cooperative. H/D exchange rates of several amide protons and four indole protons of tryptophans (W28, W108, W111, and W123), measured by refolding from 50% DMSO at different time intervals reveal that protection factors are high for the helical domain, whereas NH groups in the triple stranded antiparallel β-sheet domain are largely solvent-exposed. An ordered hydrophobic core in the intermediate state comprising of helix A, helix B, and helix D is consistent with the high protection factors observed. The structured intermediate in 50% DMSO resembles the early kinetic intermediate observed in the refolding of hen egg white lysozyme, as well as a molten globule state of equine lysozyme at low pH. The results demonstrate the potential use of nonaqueous structure perturbing solvents like DMSO to stabilize partially folded conformations of proteins. Proteins 29:492-507, 1997. © 1997 Wiley-Liss, Inc.
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  • 174
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 508-516 
    ISSN: 0887-3585
    Keywords: conformational changes ; compact and flat native structures ; metastable states ; lattice model ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We present the results of lattice Monte Carlo simulations of protein folding in the framework of a model taking into account (i) the dependence of the energy of interaction of amino-acid residues on their orientation and (ii) the rigidity of the polypeptide chain with respect to the formation of kinks. If the chain is flexible, the final protein structures are predicted to be compact. Increasing the energy cost of creation of kinks is found to favor the formation of flat structures mimicking an ideal antiparallel β sheet. For compact structures, the kinetics of folding exhibit the standard two-phase regime (a rapid collapse to one of the metastable state, followed by slow reconfiguration of the chain to the native structure). For flat structures, the transition to the native state is often gradual. Proteins 29:508-516, 1997. © 1997 Wiley-Liss, Inc.
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  • 175
    ISSN: 0887-3585
    Keywords: cellulosome ; cellulases ; cohesin domain ; scaffoldin subunit ; EF-hand motif ; molecular modeling ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The cross-species specificity of the cohesin-dockerin interaction, which defines the incorporation of the enzymatic subunits into the cellulosome complex, has been investigated. Cohesin-containing segments from the cellulosomes of two different species, Clostridium thermocellum and Clostridium cellulolyticum, were allowed to interact with cellulosomal (dockerin-containing) enzymes from each species. In both cases, the cohesin domain of one bacterium interacted with enzymes from its own cellulosome in a calcium-dependent manner, but the same cohesin failed to recognize enzymes from the other species. Thus, in the case of these two bacteria, the cohesin-dockerin interaction seems to be species-specific. Based on intra- and cross-species sequence comparisons among the different dockerins together with their known specificities, we tender a prediction as to the amino-acid residues critical to recognition of the cohesins. The suspected residues were narrowed down to only four, which comprise a repeated pair located within the calcium-binding motif of two duplicated sequences, characteristic of the dockerin domain. According to the proposed model, these four residues do not participate in the binding of calcium per se; instead, they appear to serve as recognition codes in promoting interaction with the cohesin surface. Proteins 29:517-527, 1997. © 1997 Wiley-Liss, Inc.
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  • 176
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 545-552 
    ISSN: 0887-3585
    Keywords: BTK ; XLA ; SH3 domain ; TH domain ; proline-rich peptide ; p120cbl ; peptide binding ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: X-linked agammaglobulinemia (XLA), an inherited disease, is caused by mutations in the Bruton's tyrosine kinase (BTK). The absence of functional BTK leads to failure of B-cell differentiation; this incapacitates antibody production in XLA patients, who suffer from recurrent, sometimes lethal, bacterial infections. BTK plays an important role in B-cell development; it interacts with several proteins in the context of signal transduction. Point mutation in the BTK gene that leads to deletion of C-terminal 14 aa residues of BTK SH3 domain was found in a patient family. To understand the role of BTK, we studied binding of BTK SH3 domain (aa 216-273, 58 residues) and truncated SH3 domain (216-259, 44 residues) with proline-rich peptides; the first peptide constitutes the SH3 domain of BTK, while the latter peptide lacks 14 amino acid residues of the C terminal. Proline-rich peptides selected from TH domain of BTK and p120cbl were studied. It is known that BTK TH domain binds to SH3 domains of various proteins. We found that BTK SH3 domain binds to peptides of BTK TH domain. This suggests that BTK SH3 and TH domains may associate in inter- or intramolecular fashion, which raises the possibility that the kinase may be regulating its own activity by restricting the availability of both its ligand-binding modules. We also found that truncated SH3 domain binds to BTK TH domain peptide less avidly than does normal SH3 domain. Also, we show that the SH3 and truncated SH3 domains bind to peptide of p120cbl, but the latter domain binds weakly. It is likely that the truncated SH3 domain fails to present to the ligand the crucial residues in the correct context, hence the weaker binding. These results delineate the importance of C terminal in binding of SH3 domains and indicate also that improper folding and the altered binding behavior of mutant BTK SH3 domain likely leads to XLA. Proteins 29:545-552, 1997. © 1997 Wiley-Liss, Inc.
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  • 177
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 528-548 
    ISSN: 0887-3585
    Keywords: cytokines ; IL-6 ; IL-6 receptor complexes ; electrostatic potential ; homology modeling ; molecular dynamics ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Interleukin-6 (IL-6) is a multifunctional cytokine that regulates cell growth, differentiation, and cellular functions in many cell lineages. Recently, evidences for the formation of an active hexameric complex with an IL-6:IL-6Rα:gp130 stoichiometry of 2:2:2 have been obtained by different experimental approaches. Analysis of the electrostatic potential complementarity between IL-6 and its receptors has been used, in this study, to guide the assembly of homology-based 3D models of the components. The results strongly support a mechanism whereby the active cytokine (IL-6:IL-6Rα) associates with the signal transducing gp130 protein, and the trimeric complex formed further dimerizes to form the hexameric species. Furthermore, computational simulations of the multiprotein complexes provide a rationalization of data from mutation experiments and highlight some key protein-protein interactions which have not yet been the subject of mutagenesis studies. Proteins 29:528-544, 1997. © 1997 Wiley-Liss, Inc.
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  • 178
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 553-561 
    ISSN: 0887-3585
    Keywords: metal ligands ; mutagenesis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Phosphotriesterase (PTE) is a zinc metalloenzyme that catalyzes the hydrolysis of an extensive array of organophosphate pesticides and mammalian acetylcholinesterase nerve agents. Although the three-dimensional crystal structure of PTE has been solved (M. M. Benning et al., Biochemistry 34:7973-7978, 1995), the precise functions of the individual amino acid residues that interact directly with the substrate at the active site are largely unknown. To construct mutants of PTE with altered specificities for particular target substrates, a simple methodology for generating a library of mutants at specific sites was developed. In this investigation, four of the six protein ligands to the binuclear metal site (His-55, His-57, His-201, and His-230) were targeted for further characterization and investigation. Using the polymerase chain reaction (PCR) protocols, a library of modified PTE genes was generated by simultaneously creating random combinations of histidine and cysteine codons at these four positions. The 16 possible DNA sequences were isolated and confirmed by dideoxy-DNA sequencing. The 16 mutant proteins were expressed in Escherichia coli and grown with the presence or absence of 1 mM CoCl2, ZnSO4, or CdSO4in the growth medium. When grown in the presence of CoCl2, the H57C protein cell lysate showed greater activity for the hydrolysis of paraoxon than the wild type PTE cell lysate. H201C and H230C exhibited up to 15% of the wild-type activity, while H55C, a green protein, was inactive under all assay conditions. All other mutants had 〈10-5 of wild-type activity. None of the purified mutants that exhibited catalytic activity had a significantly altered Km for paraoxon. Proteins 29:553-561, 1997. © 1997 Wiley-Liss, Inc.
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  • 179
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    Keywords: hydrothermal vent ; vestimentiferan ; hemoglobin ; primary structure ; phylogenetic relationships ; sulfide binding-site ; symbiosis ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The deep-sea tube worm Riftia pachyptila Jones possesses a multi-hemoglobin system with three different extracellular Hbs: two dissolved in the vascular blood, V1 (ca. 3,500 kDa) and V2 (ca. 400 kDa), and one in the coelomic fluid, C1 (ca. 400 kDa). V1 Hb consists of four heme-containing, globin chains (b-e) and four linker chains (L1-L4). V2 and C1 Hbs are exclusively built from globin chains, six for V2 (a-f) and five for C1 (a-e). The complete amino acid sequence of the isolated monomeric globin chain b, common to all Riftia Hbs, has been determined by automated Edman degradation sequencing of the peptides derived by digestion with trypsin, chymotrypsin, thermolysin, and CNBr. This polypeptide chain is composed of 144 amino acid residues, providing a Mr of 16, 135.0 Da. Moreover, the primary sequence of chain b revealed 3 Cys residues at position 4, 75, and 134. Cys-4 and Cys-134 are located at positions where an intra-chain disulfide bridge is formed in all annelid, vestimentiferan, or pogonophoran chains, but Cys-75 is located at a unique position only found in three globin chains belonging to Lamellibrachia and Oligobrachia, a vestimentiferan and a pogonophoran. In both groups, Hbs can bind sulfide reversibly to fuel the chemosynthetic process of the symbiotic bacteria they harbor. Sulfide-binding experiments performed on purified Hb fractions (i.e., V1, V2, and C1 Hbs) suggest that free Cys residues on globin chains, and the numerous Cys found in linker chains, as determined previously by ESI-MS, may be the sulfide binding-sites. Blocking the free Cys by N-ethylmaleimide, we confirmed that free cysteines were involved in sulfide-binding but did not account for the whole sulfide-binding capacity of V1 Hb. Furthermore, a phylogenetic tree was constructed from 18 globin-like chains of annelid, vetimentiferan, and pogonophoran extracellular Hbs to clarify the systematic position of tubeworms. Riftia chain b clearly belongs to the “strain A” family with 30 to 80% identity with the other sequences analyzed. Its position in the tree confirmed a close relationship between vestimentiferan, pogonophoran, and annelid Hbs. Proteins 29:562-574, 1997. © 1997 Wiley-Liss, Inc.
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  • 180
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 1-1 
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: No abstract.
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  • 181
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 2-6 
    ISSN: 0887-3585
    Keywords: protein structure prediction ; community-wide experiment ; CASP ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: No abstract.
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  • 182
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 575-582 
    ISSN: 0887-3585
    Keywords: 310 helix ; r Aib residue ; polypeptides ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Computer simulations have been used to design a polypeptide with a 310 helix conformation. The study has been been performed taking advantage of the intrinsic helix forming tendency of α-Aminoisobutyric acid. In order to avoid the formation of the α helix, which is the other common helical conformation adopted by α-Aminoisobutyric acid-based peptides, retropeptide bonds have been included in the sequence. Thus, retropeptides are not able to form the intramolecular hydrogen bonding interactions characteristic of the α helix. The influences of both the peptide length and the solvent have been examined and compared with those of the polypeptide without retropeptide bonds. Proteins 29:575-582,1997. © 1997 Wiley-Liss, Inc.
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  • 183
    ISSN: 0887-3585
    Keywords: deformation zones ; prediction map building ; homology modeling ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Five models by homology containing insertions and deletions and ranging from 33% to 48% sequence identity to the known homologue, and one high sequence identity (85%) model were built for the CASP2 meeting. For all five low identity targets: (i) our starting models were improved by the Internal Coordinate Mechanics (ICM) energy optimization, (ii) the refined models were consistently better than those built with the automatic SWISS-MODEL program, and (iii) the refined models differed by less than 2% from the best model submitted, as judged by the residue contact area difference (CAD) measure [Abagyan, R.A., Totrov, M.J. Mol. Biol. 268:678-685, 1997]. The CAD measure is proposed for ranking models built by homology instead of global root-mean-square deviation, which is frequently dominated by insignificant yet large contributions from incorrectly predicted fragments or side chains. We demonstrate that the precise identification of regions of local backbone deviation is an independent and crucial step in the homology modeling procedure after alignment, since aligned fragments can strongly deviate from the template at various distances from the alignment gap or even in the ungapped parts of the alignment. We show that a local alignment score can be used as an indicator of such local deviation. While four short loops of the meeting targets were predicted by database search, the best loop 1 from target T0028, for which the correct database fragment was not found, was predicted by Internal Coordinate Mechanics global energy optimization at 1.2 Å accuracy. A classification scheme for errors in homology modeling is proposed. Proteins, Suppl. 1:29-37, 1997.© 1998 Wiley-Liss, Inc.
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  • 184
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 43-49 
    ISSN: 0887-3585
    Keywords: graph theory ; clique-finding ; comparative modeling ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: We constructed five comparative models in a blind manner for the second meeting on the Critical Assessment of protein Structure Prediction methods (CASP2). The method used is based on a novel graph-theoretic clique-finding approach, and attempts to address the problem of interconnected structural changes in the comparative modeling of protein structures. We discuss briefly how the method is used for protein structure prediction, and detail how it performs in the blind tests. We find that compared to CASP1, significant improvements in building insertions and deletions and sidechain conformations have been achieved. Proteins, Suppl. 1:43-49, 1997. © 1998 Wiley-Liss, Inc.
    Additional Material: 1 Ill.
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  • 185
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 14-28 
    ISSN: 0887-3585
    Keywords: comparative modeling ; model assessment ; protein ; structure ; CASP2 ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: An assessment is presented for all submissions to the comparative modeling challenge in the 1996 Critical Assessment of Structure Prediction (CASP2). Of the original 12 target structures, 9 were solved prior to the meeting: 8 by X-ray crystallography and 1 by NMR spectroscopy. These targets varied over a large range of difficulty, as assessed by the percentage sequence identity with the principal parent structure, which ranged from 20% up to 85%. The overall quality of the models reflected the similarity of the principal parent. As expected, when the sequence alignment was correct, the core was accurately modeled, with the largest deviations occurring in the loops. Models were built which gave Cα root-mean-square deviations (RMSDs) compared with the observed structure of 〈1 Å for targets with high parental similarity; even at 26% sequence identity, the best model structures had Cα deviations of only 2.2 Å. Overall, these deviations are comparable with those observed between the parent structure and the target, but locally there are several examples where the model approaches closer to the target than does the parent. There were three targets below 25% sequence identity, and the models generated for these targets were, in general, significantly less accurate. This principally reflects errors in the alignment which, if systematically shifted, can generate Cα RMSDs 〈18 Å. Compared with CASP1, the geometry of the models was significantly improved with no D-amino acids. By far the major contribution to RMSD error was the alignment accuracy, which varied from 100% down to 7% over the range of targets. In the structurally variable regions, global shifts, caused by hinge bending, were the major source of error, giving significantly lower local RMSDs than global RMSDs. In over 50% of these noncore regions, the difference between global and local RMSDs was more than 3 Å, and was as high as 10 Å for one structurally variable region. For the side chains, the χ1 RMSDs are strongly correlated with the Cα RMSDs. For models with Cα deviations less than 1 Å, on average 78.5% of side chains are placed in the correct rotamer, although the χ1 RMSDs, though clearly better than random, were disappointing at around 46°. As the backbone deviations increased, the side chain placement became less accurate, with an average χ1 RMSD of 75° on a 1.5-2.5 Å Cα backbone (average 51.4% correct rotamer). Refinement by energy minimization or molecular dynamics made only minor adjustments to improve local geometry and generally made small, but not significant, improvements to the RMSD. In total, 19 groups submitted 62 models (89 coordinate sets) that could be assessed. Most modelers used manual adjustments to sequence alignments and, in general, good alignments were obtained down to 25% sequence identity. The modeling methods ranged from “classical” modeling, involving core building followed by loop and side chain addition, to more sophisticated approaches based on probability distributions, Monte Carlo sampling or distance geometry. For each target, several groups produced equally good models, given the expected errors in the structures (about 0.5 Å). No one method came out as clearly superior, although the approaches that inherit directly from the parents generally performed better than the more radical techniques. However, for each target there were some poor models, usually reflecting a poor sequence alignment, and the range of accuracy for each target is therefore large. Fully automated methods are able to perform very well for “easy” targets (85% sequence identity with parent), but when modeling using a distantly related parent, care and expertise, especially in performing the alignment, still appear to be important factors in generating accurate models. Proteins, Suppl. 1:14-28, 1997. © 1998 Wiley-Liss, Inc.
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  • 186
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    Proteins: Structure, Function, and Genetics 29 (1997), S. 68-73 
    ISSN: 0887-3585
    Keywords: homology modeling ; energy minimization ; distance restraints ; protein structure ; prediction errors ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Comparative modeling targets 1, 3, 9, and 17 were predicted by alignment of multiple sequences and structures, when available, followed by minimization using the program AMMP. The minimization used improved potentials, and distance restraints for regions of common structure. New prediction procedures were evaluated. Three tested solvent corrections did not significantly improve the predictions. Target 17 had 85.3% sequence identity with the parent and no insertions or deletions. The prediction had a root-mean-square deviation from target 17 of 0.56 Å on Cα atoms, and 0.59 Å for the ligand atoms, which verified the accuracy of the minimization. Targets 1, 3, and 9 had 36.4%, 46.7%, and 33.3% identity with the parent sequences, and predictions resulted in root-mean-square deviations for 79-85% of Cα atoms of 1.49, 1.11, and 1.24 Å, respectively. Conformational differences between parent and target crystal structures were difficult to predict. The use of distance restraints and multiple structures improved the positioning of gaps in sequence alignment. Distance restraints did not overcome errors in sequence alignment or ambiguities due to conformational variation in proteins. Predictions for targets 3 and 9 successfully reduced large deviations between parent and target structures. Proteins, Suppl. 1:68-73, 1997. © 1998 Wiley-Liss, Inc.
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  • 187
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    Proteins: Structure, Function, and Genetics 27 (1997), S. i 
    ISSN: 0887-3585
    Keywords: Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: No abstract.
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  • 188
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 165-170 
    ISSN: 0887-3585
    Keywords: α helix ; secondary structure ; gas phase ; molecular mechanics ; mass spectrometry ; kinetic energy release ; melittin ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The stability of the α helix as an element of secondary structure is examined in the absence of solvation, in the gas phase. Mass-analyzed ion kinetic energy (MIKE) spectrometry was applied to measure intercharge repulsion and intercharge distance in multiply protonated melittin, a polypeptide known to possess a stable helical structure in a number of different environments. The experimental results, interpreted in combination with molecular mechanics calculations, suggest that triply charged melittin retains its secondary structure in the gas phase. The stability if the α-helical conformation of the polypeptide in the absence of solvent molecules reflects the fact that a network of intrinsic helical hydrogen bonds is energetically more favorable than unfolded conformations. © 1997 Wiley-Liss, Inc.
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  • 189
    ISSN: 0887-3585
    Keywords: aspartic protease ; HIV-1 ; complex with inhibitor ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The structure of a complex between a hexapeptide-based inhibitor, MVT-101, and the chemically synthesized (Aba 67,95,167,195; Aba: l-α-amino-n-butyric acid) protease from the human immunodeficiency virus (HIV-1), reported previously at 2.3 Å has now been refined to a crystallographic R factor of 15.4% at 2.0 Å resolution. Root mean square deviations from ideality are 0.18 Å for bond lengths and 2.4° for the angles. The inhibitor can be fitted to the difference electron density map in two alternative orientations. Drastic differences are observed for positions and interactions at P3/S3 and P3′/S3′ subsites of the two orientations due to different crystallographic environments. © 1997 Wiley-Liss, Inc.
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  • 190
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 195-203 
    ISSN: 0887-3585
    Keywords: aspartic protease ; HIV-1 ; molecular dynamics ; molecular modeling ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Six models of the catalytic site of HIV-1 protease complexed with a reduced peptide inhibitor, MVT-101, were investigated. These studies focused on the details of protonation of the active site, its total net charge and hydrogen bonding pattern, which was consistent with both the observed coplanar configuration of the acidic groups of the catalytic aspartates (Asp-25 and Asp-125) and the observed binding mode of the inhibitor. Molecular dynamic simulations using AMBER 4.0 indicated that the active site should be neutral. The planarity of the aspartate dyad may be due to the formation of two hydrogen bonds: one between the inner Oδ1oxygen atoms of the two catalytic aspartates and another between the Oδ2atom of Asp-125 and the nitrogen atom of the reduced peptide bond of the bound inhibitor. This would require two additional protonations, either of both aspartates, or of one Asp and the amido nitrogen atom of Nle-204. Our results favor the Asp-inhibitor protonation but the other one is not excluded. Implications of these findings for the mechanism of enzymatic catalysis are discussed. Dynamic properties of the hydrogen bond network in the active site and an analysis of the interaction energy between the inhibitor and the protease are presented. © 1997 Wiley-Liss, Inc.
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  • 191
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 210-212 
    ISSN: 0887-3585
    Keywords: rab7 ; crystal ; GDP ; GTP ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The GTP/GDP conformational switch of members of the rab family of ras-related GTP-ases control specific intracellular vesicle transport pathways. We report the crystallization of the late-endosomal rab protein rab7, in both GTP and GDP conformations. X-ray data from crystals of rab71-207GppNHp (i.e., intact rab7, without C-terminal bound lipid, complexed with a non-hydrolysable GTP analog), rab71-197GppNHp and rab71-197GDP were collected to 1.9Å (0°C), 1.76Å (100°K) and 1.75Å (100°K) respectively. Rab7-GDP crystals diffract to at least 1.35Å. © 1997 Wiley-Liss, Inc.
    Additional Material: 1 Tab.
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  • 192
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 227-233 
    ISSN: 0887-3585
    Keywords: peptide conformation ; ramachandran plot ; PDB search ; peptide dynamics ; BPTI ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A simple method is presented for projecting the conformation of extended secondary structure elements of peptides and proteins that extend over four Cαatoms onto a simple two-dimensional surface. A new set of two degrees of freedom is defined, a pseudo-dihedral involving four sequential Cαatoms, as well as the triple scalar product for the vectors describing the orientation of the three intervening peptide groups. The method provides a reduction in dimensionality, from the usual combination of multiple φ,ψ pairs to a single pair, yielding valuable information concerning the structure and dynamics of these important elements. The new two-dimensional surface is explored by reference to 63 selected protein crystal structures together with a comparison of model built peptides representing the common secondary structural elements. Dynamical aspects on this new surface are examined using a molecular dynamics trajectory of Basic Pancreatic Trypsin Inhibitor. © 1997 Wiley-Liss, Inc.
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  • 193
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 235-248 
    ISSN: 0887-3585
    Keywords: acarviosinide ; active site ; docking ; glucoamylase ; molecular mechanics ; monosaccharides ; simulated annealing ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Glucoamylase is an important industrial glucohydrolase with a large specificity range. To investigate its interaction with the monosaccharides D-glucose, D-mannose, and D-galactose and with the substrate analogues 1-deoxynojirimycin, D-glucono-1,5-lactone, and methyl αacarviosinide, MM3(92)-optimized structures were docked into its active site using AutoDock 2.1. The results were compared to structures of glucoamylase complexes obtained by protein crystallography. Charged forms of some substrate analogues were also docked to assess the degree of protonation possessed by glucoamylase inhibitors. Many forms of methyl αa-carviosinide were conformationally mapped by using MM3(92), characterizing the conformational pH dependence found for the acarbose family of glucosidase inhibitors. Their significant conformers, representing the most common states of the inhibitor, were used as initial structures for docking. This constitutes a new approach for the exploration of binding modes of carbohydrate chains. Docking results differ slightly from x-ray crystallographic data, the difference being of the order of the crystallographic error. The estimated energetic interactions, even though agreeing in some cases with experimental binding kinetics, are only qualitative due to the large approximations made by AudoDock force field. © 1997 Wiley-Liss, Inc.
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  • 194
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 279-289 
    ISSN: 0887-3585
    Keywords: protein structure prediction ; prediction contest ; protein sequence alignment ; compensatory covariation ; CASP2 ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A secondary structure has been predicted for the C termini of the fibrinogen β and γ chains from an aligned set of homologous protein sequences using a transparent method that extracts conformational information from patters of variation and conservation, parsing strings, and patterns of amphiphilicity. The structure is modeled to form two domains, the first having a core parallel sheet flanked on one side by at least two helices and on the other by an antiparallel amphiphilic sheet, with an additional helix connecting the two sheets. The second domain is built entirely from β strands. © 1997 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
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  • 195
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 290-308 
    ISSN: 0887-3585
    Keywords: protein folding ; protein structure ; supersecondary structure ; structure prediction ; turn prediction ; statistical potentials ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A simple method for predicting the location of surface loops/turns that change the overall direction of the chain that is, “U” turns, and assigning the dominant secondary structure of the intervening transglobular blocks in small, single-domain globular proteins has been developed. Since the emphasis of the method is on the prediction of the major topological elements that comprise the global structure of the protein rather than on a detailed local secondary structure description, this approach is complementary to standard secondary structure prediction schemes. Consequently, it may be useful in the early stages of tertiary structure prediction when establishment of the structural class and possible folding topologies is of interest. Application to a set of small proteins of known structure indicates a high level of accuracy. The prediction of the approximate location of the surface turns/loops that are responsible for the change in overall chain direction is correct in more than 95% of the cases. The accuracy for the dominant secondary structure assignment for the linear blocks between such surface turns/loops is in the range of 82%. © 1997 Wiley-Liss, Inc.
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  • 196
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 311-314 
    ISSN: 0887-3585
    Keywords: thermostability ; cubic ; trypsin-agarose/sepharose chromatography vapor diffusion method ; self-rotation function ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Crystals of lima bean trypsin inhibitor (LBTI) were obtained by using the vapor phase equilibration technique with sodium/potassium tartrate as the precipitating agent. The space group was determined to be cubic, I213 with a= 110.2 Å. These crystals diffract to about 1.9 Å resolution. Preliminary analysis of self-rotation maps (calculated from native x-ray intensity data) suggests the presence of two monomers in the asymmetric unit. LBTI is very thermostable and retains activity even after boiling for 10 minutes. This property is exploited as part of its purification procedure. © 1997 Wiley-Liss, Inc.
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  • 197
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 315-318 
    ISSN: 0887-3585
    Keywords: catalytic domain ; cross-linking ; hanging drop ; p21 ; seeding ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Ras-GTPase-activating proteins (Ras-GAPs) are important regulators of the biological activity of Ras within the framework of intracellular communication where GTP-bound Ras (Ras: GTP) is a key signal transducing molecule (Trahey and McCormick, Science 238:542-545, 1987; Boguski and McCormick, Nature 366:643-654, 1993). By accelerating Ras-mediated GTP hydrolysis, Ras-GAPs provide an efficient means to reset the Ras-GTPase cycle to the GDP-bound “OFF”-state and terminate the Ras-mediated signal. Here we report the crystallization of the GTPase-activating domain of the human p120GAP. The crystals belong to the orthorhombic space group symmetry P212121with unit cell dimensions of a = 42.2 Å, b = 55.6 Å, c = 142.2 Å, α = β = γ = 90°. Assuming a Matthews parameter of 2.2 Å3/Da, there is one molecule per asymmetric unit. Applying micro-seeding techniques, we grew large single crystals that could not be obtained by other routine methods for crystal improvement. They diffracted to a resolution of approximately 3 Å using X-rays from a rotating anode generator and to better than 1.8 Å in a synchrotron beam. Chemical cross-linking led to reduction of the maximum resolution but to significantly increased stability against mechanical and heavy atom stress. © 1997 Wiley-Liss, Inc.
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  • 198
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 325-327 
    ISSN: 0887-3585
    Keywords: transcriptional control ; cell-cycle ; DNA-binding ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: A 124-residue N-terminal fragment corresponding to the DNA-binding domain of the Saccharomyces cerevisae cell-cycle transcription factor MBP-1 has been expressed with a hexahistidine affinity tag in E. coli and purified to apparent homogeneity. Crystals have been grown using PEG 3350 as precipitant which diffract x-rays to greater than 2.6 Å resolution. The space group is tetragonal, P43212 or P41212 with unit cell dimensions a= b= 42.2 Å, c= 123.2 Å and a monomer in the asymmetric unit. © 1997 Wiley-Liss, Inc.
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  • 199
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    Proteins: Structure, Function, and Genetics 27 (1997), S. 329-335 
    ISSN: 0887-3585
    Keywords: protein structure ; protein sequence analysis ; hydrogen bonds ; sequence alignment ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: In this study we present an accurate secondary structure prediction procedure by using a query and related sequences. The most novel aspect of our approach is its reliance on local pairwise alignment of the sequence to be predicted with each related sequence rather than utilization of a multiple alignment. The residue-by-residue accuracy of the method is 75% in three structural states after jack-knife tests. The gain in prediction accuracy compared with the existing techniques, which are at best 72%, is achieved by secondary structure propensities based on both local and long-range effects, utilization of similar sequence information in the form of carefully selected pairwise alignment fragments, and reliance on a large collection of known protein primary structures. The method is especially appropriate for large-scale sequence analysis efforts such as genome characterization, where precise and significant multiple sequence alignments are not available or achievable. Proteins 27:329-335, 1997. © 1997 Wiley-Liss, Inc.
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  • 200
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    Proteins: Structure, Function, and Genetics 28 (1997), S. 29-40 
    ISSN: 0887-3585
    Keywords: molecular evolution ; nicotinamide adenine dinucleotide ; nicotinamide adenine dinucleotide phosphate ; dinucleotide bonding domains ; mononucleotide binding domains ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Nicotinamide adenine dinucleotides [NAD and NADP with both referred to as NAD(P)] are among the more diffuse redox cofactors. Despite their stereochemical similarity where the only difference is a phosphomonoester on the ribose near the adenine of NADP, they show different biochemical reactivities with NAD behaving as an oxidant and NADP as a reductant. NAD(P)-dependent enzymes generally share a common open α/β fold with few exceptions only recently structurally characterized. This study of the molecular evolution of the NAD(P) binding domains, possible given the large number of known molecular structures, addresses two main questions: 1) can a common fold exist in different biological systems (divergent evolution) and 2) does a relationship exist among similar biological systems that display different folds (convergent evolution)? Both the structures of mono- and dinucleotide binding domains have been classified by cluster analysis based on the similarity evaluated by their main chain Cα superposition. Moreover, the cofactor conformations and the stereochemical characteristics of their pockets have also been classified by analogous methods on the basis of the published tertiary structures. Two primary results appear: 1) the classification of the mononucleotide binding domains is different from that of the dinucleotide binding folds and 2) both divergent and convergent evolutionary pathways can be hypothesized, the latter less frequently observed and less pronounced but nevertheless evident. The generally accepted hypothesis that dinucleotide binding domains have evolved by gene duplication of primordial genes coding for the smaller mononucleotide binding domains is acceptable but the two halves of the resulting dinucleotide binding domains are evolutionarly uncorrelated. The NH2-terminal mononucleotide binding domain is less variable than the COOH-terminal half, probably because it involves the binding of the ADP moiety of NAD(P) invariant in all examined systems. There is evidence to postulate that evolutionary pathways for NAD(P)-dependent enzymes are both divergent and convergent. In fact, nearly all combinations of similarity/dissimilarity in overall fold, cofactor conformation, and cofactor binding pocket structural characteristics for each enzyme pair examined are possible. The NAD(P)-dependent enzymes apparently provide a canonical example of an evolutionary principle that “anything goes.” © 1997 Wiley-Liss Inc.
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