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21.
Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1'' binding site.
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J H Matthews R Krishnan M J Costanzo B E Maryanoff A Tulinsky 《Biophysical journal》1996,71(5):2830-2839
Structures of the blood clotting enzyme thrombin complexed with hirugen and two active site inhibitors, RWJ-50353 10080(N-methyl-D-phenylalanyl-N-[5-[(aminoiminomethyl)amino]-1- [[(2-benzothiazolyl)carbonyl]butyl]-L-prolinamide trifluoroacetate hydrate) and RWJ-50215 (N-[4-(aminoiminomethyl)amino-1-[2- (thiazol-2-ylcarbonylethyl)piperidin- 1-ylcarbonyl]butyl]-5-(dimethylamino)naphthalenesulfonamide trifluoroacetate hydrate), were determined by x-ray crystallography. The refinements converged at R values of 0.158 in the 7.0-2.3-A range for RWJ-50353 and 0.155 in the 7.0-1.8-A range for RWJ-50215. Interactions between the protein and the thiazole rings of the two inhibitors provide new valuable information about the S1' binding site of thrombin. The RWJ-50353 inhibitor consists of an S1'-binding benzothiazole group linked to the D-Phe-Pro-Arg chloromethyl ketone motif. Interactions with the S1-S3 sites are similar to the D-phenylalanyl-prolyl-arginyl chloromethylketone structure. In RWJ-50215, a S1'-binding 2-ketothiazole group was added to the thrombin inhibitor-like framework of dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. The geometry at the S1-S3 sites here is also similar to that of the parent compound. The benzothiazole and 2-ketothiazole groups bind in a cavity surrounded by His57, Tyr60A, Trp60D, and Lys60F. This location of the S1' binding site is consistent with previous structures of thrombin complexes with hirulog-3, CVS-995, and hirutonin-2 and -6. The ring nitrogen of the RWJ-50353 benzothiazole forms a hydrogen bond with His57, and Lys60F reorients because of close contacts. The oxygen and nitrogen of the ketothiazole of RWJ-50215 hydrogen bond with the NZ atom of Lys60F. 相似文献
22.
The effect of structural changes in the N-terminal amino acid of AIV, with respect to AT4 receptor binding, was examined by competition with [125I]AIV in bovine adrenal membranes. Analogues with modifications of the first residue α-amino group possessed lower affinities than the primary amine-containing parent compound. Peptides with a residue 1 α-carbon in the d conformation exhibited poor affinity for the AT4 receptor. Modifications of the residue 1 R-group demonstrate that a straight chain aliphatic moiety containing four carbons is optimal for receptor-ligand binding, as evidenced by the extremely high affinity of [Nle1]AIV (Ki = 3.59±0.51 pM). Replacement of the 1–2 peptide bond of AIV with the methylene bond isostere Ψ (CH2-NH), increased the Ki approximately fivefold, indicating that the peptide bond may be replaced wihle maintaining relatively high-affinity receptor binding. 相似文献
23.
The effect of structural changes in the N-terminal amino acid of AIV, with respect to AT4 receptor binding, was examined by competition with [125I]AIV in bovine adrenal membranes. Analogues with modifications of the first residue -amino group possessed lower affinities than the primary amine-containing parent compound. Peptides with a residue 1 -carbon in the
conformation exhibited poor affinity for the AT4 receptor. Modifications of the residue 1 R-group demonstrate that a straight chain aliphatic moiety containing four carbons is optimal for receptor-ligand binding, as evidenced by the extremely high affinity of [Nle1]AIV (Ki = 3.59±0.51 pM). Replacement of the 1–2 peptide bond of AIV with the methylene bond isostere Ψ (CH2-NH), increased the Ki approximately fivefold, indicating that the peptide bond may be replaced wihle maintaining relatively high-affinity receptor binding. 相似文献
24.
Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. 总被引:9,自引:2,他引:7
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O Colamonici H Yan P Domanski R Handa D Smalley J Mullersman M Witte K Krishnan J Krolewski 《Molecular and cellular biology》1994,14(12):8133-8142
25.
Halotolerance of Methanobacterium thermoautotrophicum delta H and Marburg. 总被引:1,自引:1,他引:0
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R Ciulla C Clougherty N Belay S Krishnan C Zhou D Byrd M F Roberts 《Journal of bacteriology》1994,176(11):3177-3187
Methanobacterium thermoautotrophicum delta H and Marburg were adapted to grow in medium containing up to 0.65 M NaCl. From 0.01 to 0.5 M NaCl, there was a lag before cell growth which increased with increasing external NaCl. The effect of NaCl on methane production was not significant once the cells began to grow. Intracellular solutes were monitored by nuclear magnetic resonance (NMR) spectroscopy as a function of osmotic stress. In the delta H strain, the major intracellular small organic solutes, cyclic-2,3-diphosphoglycerate and glutamate, increased at most twofold between 0.01 and 0.4 M NaCl and decreased when the external NaCl was 0.5 M. M. thermoautotrophicum Marburg similarly showed a decrease in solute (cyclic-2,3-diphosphoglycerate, 1,3,4,6-tetracarboxyhexane, and L-alpha-glutamate) concentrations for cells grown in medium containing > 0.5 M NaCl. At 0.65 M NaCl, a new organic solute, which was visible in only trace amounts at the lower NaCl concentrations, became the dominant solute. Intracellular potassium in the delta H strain, detected by atomic absorption and 39K NMR, was roughly constant between 0.01 and 0.4 M and then decreased as the external NaCl increased further. The high intracellular K+ was balanced by the negative charges of the organic osmolytes. At the higher external salt concentrations, it is suggested that Na+ and possibly Cl- ions are internalized to provide osmotic balance. A striking difference of strain Marburg from strain delta H was that yeast extract facilitated growth in high-NaCl-containing medium. The yeast extract supplied only trace NMR-detectable solutes (e.g., betaine) but had a large effect on endogenous glutamate levels, which were significantly decreased. Exogenous choline and glycine, instead of yeast extract, also aided growth in NaCl-containing media. Both solutes were internalized with the choline converted to betaine; the contribution to osmotic balance of these species was 20 to 25% of the total small-molecule pool. These results indicate that M. thermoautotrophicum shows little changes in its internal solutes over a wide range of external NaCl. Furthermore, they illustrate the considerable differences in physiology in the delta H and Marburg strains of this organism. 相似文献
26.
A rapid propagation method comprising initiation of in vitro shoot tip culture from field-grown flowering plants and reculture of the nodal segments of regenerated shoots in Schenk and Hildebrandt (1972) medium was developed for Woodfordia fruticosa (L.) Kurz., a rare medicinal shrub. A medium supplement of 6-benzylaminopurine (0.2 mg.l–1) induced high frequency (88%) development of axillary shoot buds (3.2) in 4–5 weeks. Subculture of the explants with multiple new shoots in fresh medium for 30 days yielded an even larger number (9.7) of shoots. Highest multiplication (26–35 shoots) was recorded when using culture initiation media with 0.5 mg.l–1 each of BAP and NAA followed by subculture in 0.2 mg.l–1 BAP. The shoot multiplication rate was further accelerated by reculturing 0.4–0.6 cm nodal segments of regenerated shoots in media with 1.0 mg.l–1 BAP. Shoot cuttings (3.5–7.0 cm) were rooted in 0.2 mg.l–1 IAA. Regenerated plants displayed uniform morphological, growth and flowering characteristics.Abbreviations BAP
6-benzylaminopurine
- NAA
naphthaleneacetic acid
- IAA
Indole-3-acetic acid
- IBA
indole-3-butyric acid
- SH
Schenk and Hildebrandt (1972) medium 相似文献
27.
D. Mayilvahanan G. Annadurai V. Raju M. Chellapandian M. R. V. Krishnan Kunthala Jayaraman 《Bioprocess and biosystems engineering》1996,15(6):323-326
Techniques for possible higher and rapid production of citric acid from the well known industrial medium i.e. molasses has
been reported using Aspergillus niger. This includes optimization of the total reducing sugar (TRS) and nutrients like nitrogen
and phosphorous. The long and unproductive lag periods normally associated with this type of fermentation has been reduced.
These strategies are discussed in detail.
Dr. M. Chellapandian is thankful to the Council of Scientific and Industrial Research, New Delhi, for the award of research
associateship. 相似文献
28.
A Genetic and Mosaic Analysis of a Locus Involved in the Anesthesia Response of Drosophila Melanogaster
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We describe a genetic and behavioral analysis of several alleles of har38, a mutant with altered sensitivity to the general anesthetic halothane. We obtained a P-element-induced allele of har38 and generated several excision alleles by remobilizing the P element. The mutants narrow abdomen (na) and har85 are confirmed to be allelic to har38. Besides a decreased sensitivity to halothane, all mutant alleles of this locus cause a characteristic walking behavior in the absence of anesthetics. We have quantified this behavior using a geotaxis apparatus. Responses of the mutant alleles to different inhalational anesthetics were tested. The results strongly favor a multipathway model for the onset of anesthesia. Mosaic flies were tested for their response to halothane and checked for their abnormal walking behavior. The analysis suggests that both the behaviors are exhibited only by such mosaics as have the entire head of mutant origin. It is likely that this focus represents an element of a common pathway in the anesthetic response to several inhalational anesthetics but not all. This result is the first demonstration of regional specificity in the CNS of any animal for general anesthetic action. 相似文献
29.
Krishnan Bharath S.; Clemens Ron E.; Zintel Trevor A.; Stockwell Martin J.; Gallagher Charles G. 《Journal of applied physiology》1997,83(1):82-88
Krishnan, Bharath S., Ron E. Clemens, Trevor A. Zintel,Martin J. Stockwell, and Charles G. Gallagher. Ventilatory response to helium-oxygen breathing during exercise: effect of airwayanesthesia. J. Appl. Physiol. 83(1):82-88, 1997.The substitution of a normoxic helium mixture(HeO2) for room air (Air) during exercise results in a sustained hyperventilation, which is present evenin the first breath. We hypothesized that this response is dependent onintact airway afferents; if so, airway anesthesia (Anesthesia) shouldaffect this response. Anesthesia was administered to the upper airwaysby topical application and to lower central airways by aerosolinhalation and was confirmed to be effective for over 15 min. Subjectsperformed constant work-rate exercise (CWE) at 69 ± 2 (SE) % maximal work rate on a cycle ergometer on three separate days: twiceafter saline inhalation (days 1 and3) and once after Anesthesia(day 2). CWE commenced after a briefwarm-up, with subjects breathing Air for the first 5 min (Air-1),HeO2 for the next 3 min, and Airagain until the end of CWE (Air-2). The resistance of the breathingcircuit was matched for Air andHeO2. BreathingHeO2 resulted in a small butsignificant increase in minute ventilation(I) anddecrease in alveolar PCO2 in both theSaline (average of 2 saline tests; not significant) and Anesthesiatests. Although Anesthesia had no effect on the sustainedhyperventilatory response to HeO2breathing, theI transientswithin the first six breaths ofHeO2 were significantly attenuatedwith Anesthesia. We conclude that theI response to HeO2 is not simply due to areduction in external tubing resistance and that, in humans, airwayafferents mediate the transient but not the sustained hyperventilatoryresponse to HeO2 breathing duringexercise. 相似文献
30.
Effect of oilseed cakes on alpha-amylase production by Bacillus licheniformis CUMC305. 总被引:1,自引:1,他引:0
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The effects of oilseed cakes on extracellular thermostable alpha-amylase production by Bacillus licheniformis CUMC305 was investigated. Each oilseed cake was made of groundnut, mustard, sesame, linseed, coconut copra, madhuca, or cotton. alpha-Amylase production was considerably improved in all instances and varied with the oilseed cake concentration in basal medium containing peptone and beef extract. Maximum increases were effected by a low concentration (0.5 to 1.0%) of groundnut or coconut, a high concentration (3%) of linseed or mustard, and an Rintermediate concentration (2%) of cotton, madhuca, or sesame. The oilseed cakes made of groundnut or mustard could completely replace the conventional peptone-beef extract medium as the fermentation base for the production of alpha-amylase by B. licheniformis. The addition of corn steep liquor to cotton, linseed, sesame, or madhuca cake in the medium improved alpha-amylase production. 相似文献