Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sensitivity to micronucleus (MN) induction of human, mouse, and rat peripheral blood lymphocytes (PBLs) exposed to bleomycin sulfate (BLM) in vitro was compared in cytochalasin B-induced binucleated (BN) cells. For the PBLs of each species, either 0, 5, 10, 20, 40, 60, 80, or 160 micrograms/ml BLM was added to 5 ml aliquots of whole blood for 4 hr at 37 degrees C in a 5% CO2 atmosphere. Leukocytes were isolated on a density gradient and cultured in the presence of phytohemagglutinin to stimulate blastogenesis, and cytochalasin B was added to each culture at 21 hr postinitiation to prevent cytokinesis. A total of 4,000 BNs/concentration/species was analyzed for MN in two independent experiments. In addition, multiple-MN-BNs were quantitated, and the nucleation index was determined. Significant increases both in total MN-BNs and multiple-MN-BNs were observed at all concentrations in all species. All three species' concentration-response curves gave good fits (r2 values from 0.87 to 0.95) to either a linear or a square root model (y = mx + b or y = m[x]0.5 + b, respectively; where y = the percentage of MN-BN, m is the slope, and b is the y-intercept). The MN induction in the human and rat PBLs was not statistically different, but both were significantly less sensitive than the response shown by the BLM-exposed mouse PBLs. This difference in MN susceptibility was observed only at BLM test concentrations > or = 20 micrograms/ml. The nucleation index was significantly decreased in all species at either 80 or 160 micrograms/ml.
Environ Mol Mutagen 1995
PMID:Bleomycin sulfate-induced micronuclei in human, rat, and mouse peripheral blood lymphocytes. 753 77

Expression of inducible heat shock protein-70 mRNA (hsp-70 mRNA) was studied in the rat brain following systemic administration of different convulsant agents: an L-type voltage-dependent calcium channel agonist, (+/-)-BAY K 8644 (BAY-K); the excitotoxic glutamate agonists kainic acid and N-methyl-D-aspartic acid (NMDA); and the GABAA receptor complex antagonists pentylenetetrazole (PTZ) and lindane (gamma-hexaclorocyclohexane). BAY-K induced minimal hsp-70 mRNA expression in the hippocampus of convulsant rats, localized in the dentate gyrus and the pyramidal cell layer of Ammon's horn. Kainic acid treatment in rats, showing severe limbic convulsions, caused intense expression of hsp-70 mRNA and protein (HSP-70). Expression was localized in select cerebral regions, notably the pyramidal cell layer of the hippocampal CA3 field of Ammon's horn and the piriform cortex, and also the subicular complex and the amygdala, and, to a lesser extent, the entorhinal cortex, the pyramidal cell layer of CA1, several thalamic nuclei, and the parietal cortex. In contrast, systemic administration of NMDA, PTZ or lindane led to no detectable induction of hsp-70 mRNA in the rat brain, despite producing convulsions. Histological examination revealed cell injury only following kainic acid treatment. Damage was most apparent in the piriform and entorhinal cortices, pyramidal cell layer of the CA1 field, and cortical amygdaloid nuclei. BAY-K, NMDA, PTZ and lindane did not lead to any observable histopathological changes. These results show that convulsions of different aetiology do not inevitably induce hsp-70 mRNA expression or cell damage. Intense expression of hsp-70 mRNA was generally associated with regions that later showed variable degrees of nerve cell damage, although hsp-70 mRNA expression was not always predictive of subsequent cell death or survival.
Brain Res Mol Brain Res 1994 Nov
PMID:Regional expression of inducible heat shock protein-70 mRNA in the rat brain following administration of convulsant drugs. 753 33

We examined the influence of the molecular structure of four novel adamantane derivatives on their ability to block the channels of nicotinic acetylcholine (ACh) and N-methyl-D-aspartate (NMDA) receptors. The structure of the drugs is Ad-CH2-N+H2-(CH2)5-R, where Ad is adamantane and R was varied from ammonium (IEM-1754) to tert-butyldimethylammonium (IEM-1857) radical. The compounds induced double-exponential decays of postsynaptic currents in frog muscles and flickering of NMDA-activated channels, suggesting that each drug acts as a fast open-channel blocker at both types of receptors. The equilibrium dissociation constants (Kd) of the drugs for ACh-activated channels at -80 mV were similar, whereas the Kd values for NMDA-activated channels at -80 mV were 2-10 times lower. Several observations suggested that occupation of either type of channel by these compounds inhibited channel closure; the time constant (tau) of the slow component of the decay of postsynaptic currents in the presence of each compound was greater than the control tau, the IC50 of IEM-1754 for inhibition of NMDA-activated whole-cell currents was > 20 times larger than its Kd for the open channel, and a transient increase in NMDA-activated whole-cell currents was observed after washout of IEM-1754. Thus, these drugs appear to act on nicotinic ACh and NMDA receptors via similar mechanisms, although the voltage dependence of block suggested that the drugs bind at a more superficial site in the ACh-activated channel. All compounds also potently prevented NMDA-induced convulsions in mice. The ED50 of IEM-1754 was 4 times lower than the ED50 of MK-801.
Mol Pharmacol 1995 Mar
PMID:Novel adamantane derivatives act as blockers of open ligand-gated channels and as anticonvulsants. 753 80

Two types of distributions for the frequencies of occurrence of amino acids in each position of hypervariable regions CDR-1 and CDR-2 were obtained for 2,000 immunoglobulins. The results show that some positions fit an inverse power-law distribution, while others fit an exponential-type distribution. As a result of comparison with structural data in the literature it is proposed that sites in which the frequency distribution fits the inverse power law are critical to maintaining canonical shapes of the recognition regions or are involved in modulating these canonical conformations, while those sites where the distribution fits the exponential law are those which should be exclusively involved in the recognition mechanism.
J Mol Evol 1995 Jul
PMID:Distributions of the use frequencies of amino acids in the hypervariable regions of immunoglobulins. 760 93

The internal branch lengths estimated by distance methods such as neighbor-joining are shown to be biased to be short when the evolutionary rate differs among sites. The variable-invariable model for site heterogeneity fits the amino acid sequence data encoded by the mitochondrial DNA from Hominoidea remarkably well. By assuming the orangutan separation to be 13 or 16 Myr old, a maximum-likelihood analysis estimates a young date of 3.6 +/- 0.6 or 4.4 +/- 0.7 Myr (+/- 1 SE) for the human/chimpanzee separation, and these estimates turn out to be robust against differences in the assumed model for amino acid substitutions. Although some uncertainties still exist in our estimates, this analysis suggests that humans separated from chimpanzees some 4-5 Myr ago.
J Mol Evol 1995 Jun
PMID:Improved dating of the human/chimpanzee separation in the mitochondrial DNA tree: heterogeneity among amino acid sites. 764 13

We report the identification and sequence from Escherichia coli and Salmonella enterica strains of the cld gene, encoding the chain-length determinant (CLD) which confers a modal distribution of chain length on the O-antigen component of lipopolysaccharide (LPS). The distribution of chain lengths in the absence of this gene fits a model in which as the chain is extended there is a constant probability of 0.165 of transfer of growing chain to LPS core, with termination of chain extension. The data for E. coli O111 fit a model in which the CLD reduces this probability for short chains and increases it to 0.4 for longer chains, leading to a reduced number of short chain molecules but an increase in numbers of longer molecules and transfer of essentially all molecules by chain length 21. We put forward a model for O-antigen polymerase which resembles the ribosome and fatty acid synthetase in having two sites, with the growing chain being transferred from a D site onto the new unit at the R site to extend the chain and then back to the D site to repeat the process. It is proposed that the CLD protein and polymerase form a complex which has two states: 'E' facilitating extension and 'T' facilitating transfer to core. The complex is postulated to enter the E state as O-antigen polymerization starts, and to shift to the T state after a predetermined time, the CLD acting as a molecular clock. The CLD is not O-antigen or species-specific but the modal value does depend on the source of the cld gene.
Mol Microbiol 1993 Mar
PMID:Repeat unit polysaccharides of bacteria: a model for polymerization resembling that of ribosomes and fatty acid synthetase, with a novel mechanism for determining chain length. 768 79

Cholera toxin peptide 3 (CTP3) is a 15-residue peptide corresponding in sequence to an immunogenic loop on the surface of the B-subunits of both cholera toxin and the heat-labile toxin from Escherichia coli. TE33 is the Fab fragment of a monoclonal antibody elicited against CTP3. The crystal structure of the TE33-CTP3 complex at 2.3 A resolution reveals an antigen-binding pocket, 13 A deep and 13 A wide, which is lined with many aromatic residues. The N-terminal portion of the peptide antigen CTP3 forms a type II beta-turn that fits snugly into this pocket. At gln7 the peptide backbone of CTP3 forms a kink followed by an extended C-terminal chain that seals off the cleft and buries the beta-turn underneath it. All six complementarity-determining regions of TE33 contribute to the binding of CTP3. The antibody-peptide contacts include, in addition to van der Waals' interactions and hydrogen bonds, also one salt bridge and one water molecule, which mediates the interaction.
J Mol Biol 1993 Aug 20
PMID:Crystal structure of an anticholera toxin peptide complex at 2.3 A. 769 Apr 6

The evolution of bootstrap proportions (BP) with sequence length was studied using a 28S ribosomal RNA data set. For different sequence lengths, informative sites were jackknifed several times. Bootstrapping was subsequently performed on each of these subsamples. For each node, BPs so obtained were plotted against sequence length, showing the evolution of the robustness with increasing number of informative sites. For robust nodes (BP of 100%), the pattern of BPs is unvarying and is described by a simple function BP = 100 (1-e-b(x-x')), where x is the number of informative sites and b and x' are two parameters estimated using a nonlinear regression procedure. When a node has a BP < 100% and the pattern of BPs fits this function, it is possible to estimate the number of informative sites required to obtain a given average BP. The method also identifies nonrobust nodes (nonascending clusters of BP dots), for which it seems to be more cost effective and fruitful to turn to other species and/or genes rather than to continue sequencing longer gene lengths from the same species to reach a BP of 95%.
Mol Phylogenet Evol 1994 Dec
PMID:How many nucleotides are required to resolve a phylogenetic problem? The use of a new statistical method applicable to available sequences. 769 88

Two-dimensional NMR spectroscopy has been used to monitor the pH dependences of proton chemical shifts for turkey ovomucoid third domain (OMTKY3). Sample pH was varied from 7.0 to 1.4 in order to determine the apparent pKa values of all six carboxyl groups in OMTKY3. At 35 degrees C and in the presence of 10 mM KCl, the pKa values for Asp 7, Glu 19, and Asp 27 (< 2.6, 3.2, and < 2.3, respectively) are more than 1 pH unit below those for model compounds. The pKa values for Glu 10 (4.1) and Glu 43 (4.7) show more modest deviations from model compound data. The low pKa for the alpha-carboxyl group of Cys 56 (< 2.5) is attributable, at least in part, to acidification by the disulfide group. Fitting the data to a modified Hill equation [Markley, J. L. (1975) Acc. Chem. Res. 8, 70-80] reveals little evidence for interactions between the acidic groups; most Hill coefficients fall between 0.8 and 1.2, with outlying values usually obtained with data that describe incomplete transitions. Most of the very low pKa values show increases in the presence of 1.0 M KCl but, with the exception of that for glutamate 19, remain well below model compound values. pH-dependent changes in amide proton chemical shifts permitted identification of hydrogen bonds involving the side chains of Asp 7, Glu 19, and Asp 27, which may partially explain the low pKa values for these groups. These hydrogen bonds, two of which involve side chains that are well exposed to solvent, were previously identified in high-resolution X-ray studies of turkey ovomucoid third domain [Fujinaga, M., Sielecki, A. R., Read, R. J., Ardelt, W., Laskowski, M., Jr., & James, M. N. G. (1987) J. Mol. Biol. 195, 397-418]. Results of additional experiments performed at 15, 25, and 40 degrees C suggest that apparent ionization enthalpies for all carboxyl groups in OMTKY3 are about 0 +/- 2 kcal/mol. In the accompanying paper [Swint, L., & Robertson, A. D. (1995) Biochemistry 34, 4724-4732], the pH dependence of OMTKY3 stability is described and compared to expectations based on the pKa values described herein.
 ...
PMID:pH, ionic strength, and temperature dependences of ionization equilibria for the carboxyl groups in turkey ovomucoid third domain. 771 77

A relative comparison of the binding properties of different drug molecules requires their mutual superposition with respect to various alignment criteria. In order to validate the results of different alignment methods, the crystallographically observed binding geometries of ligands in the pocket of a common protein receptor have been used. The alignment function in the program SEAL that calculates the mutual superposition of molecules has been optimized with respect to these references. Across the reference data set, alignments could be produced that show mean rms deviations of approximately 1 A compared to the experimental situation. For structures with obvious skeletal similarities a multiple-flexible fit, linking common pharmacophoric groups by virtual springs, has been incorporated into the molecular mechanics program MOMO. In order to combine conformational searching with comparative alignments, the optimized SEAL approach has been applied to sets of conformers generated by MIMUMBA, a program for conformational analysis. Multiple-flexible fits have been calculated for inhibitors of ergosterol biosynthesis. Sets of different thrombin and thermolysin inhibitors have been conformationally analyzed and subsequently aligned by a combined MIMUMBA/SEAL approach. Since for these examples crystallographic data on their mutual alignment are available, an objective assessment of the computed results could be performed. Among the generated conformers, one geometry could be selected for the thrombin and thermolysin inhibitors that approached reasonably well the experimentally observed alignment.
J Comput Aided Mol Des 1994 Dec
PMID:Different approaches toward an automatic structural alignment of drug molecules: applications to sterol mimics, thrombin and thermolysin inhibitors. 773 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>