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71.
Xu J Wei L Mathvink R Edmondson SD Mastracchio A Eiermann GJ He H Leone JF Leiting B Lyons KA Marsilio F Patel RA Petrov A Wu JK Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2006,16(5):1346-1349
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. The optimized compound exhibited good pharmacokinetic profiles in three preclinical species. 相似文献
72.
Clark AT Smith K Muhandiram R Edmondson SP Shriver JW 《Journal of molecular biology》2007,372(4):992-1008
Sac7d and Sso7d are homologous, hyperthermophile proteins with a high density of charged surface residues and potential ion pairs. To determine the relative importance of specific amino acid side-chains in defining the stability and function of these Archaeal chromatin proteins, pK(a) values were measured for the acidic residues in both proteins using (13)C NMR chemical shifts. The stability of Sso7d enabled titrations to pH 1 under low-salt conditions. Two aspartate residues in Sso7d (D16 and D35) and a single glutamate residue (G54) showed significantly perturbed pK(a) values in low salt, indicating that the observed pH-dependence of stability was primarily due to these three residues. The pH-dependence of backbone amide NMR resonances demonstrated that perturbation of all three pK(a) values was primarily the result of side-chain to backbone amide hydrogen bonds. Few of the significantly perturbed acidic pK(a) values in Sac7d and Sso7d could be attributed to primarily ion pair or electrostatic interactions. A smaller perturbation of E48 (E47 in Sac7d) was ascribed to an ion pair interaction that may be important in defining the DNA binding surface. The small number (three) of significantly altered pK(a) values was in good agreement with a linkage analysis of the temperature, pH, and salt-dependence of folding. The linkage of the ionization of two or more side-chains to protein folding led to apparent cooperativity in the pH-dependence of folding, although each group titrated independently with a Hill coefficient near unity. These results demonstrate that the acid pH-dependence of protein stability in these hyperthermophile proteins is due to independent titration of acidic residues with pK(a) values perturbed primarily by hydrogen bonding of the side-chain to the backbone. This work demonstrates the need for caution in using structural data alone to argue the importance of ion pairs in stabilizing hyperthermophile proteins. 相似文献
73.
Background
There have been many algorithms and software programs implemented for the inference of multiple sequence alignments of protein and DNA sequences. The "true" alignment is usually unknown due to the incomplete knowledge of the evolutionary history of the sequences, making it difficult to gauge the relative accuracy of the programs. 相似文献74.
75.
The influence of core hydrophobicity and packing on the structure and stability of the hyperthermophile proteins Sac7d and Sso7d have been studied by calorimetry, circular dichroism, and NMR. Valine 30 is positioned in Sac7d to allow a cavity-filling Val --> Ile substitution which occurs naturally in the homologous more thermostable Sso7d. The cavity-filling mutation in Sac7d has been characterized and compared to the reciprocal Ile --> Val mutation in Sso7d. A detailed analysis of the stability of the proteins was obtained by globally fitting the variation of DSC parameters and circular dichroism intensities as a function of temperature (0-100 degrees C), salt (0-0.3 M), and pH (0-8). A global analysis over such a range of conditions permitted an unusually precise measure of the thermodynamic parameters, as well as the separation of the thermodynamics of the intrinsic unfolding reaction from the linked effects of protonation and chloride binding associated with acid-induced folding. The results indicate differences in the energetics of unfolding Sac7d and Sso7d that would not be apparent from an analysis of DSC data alone using conventional methods. The sign and magnitude of the changes in DeltaG, DeltaH, TDeltaS, and DeltaC(P) of unfolding resulting from core Ile/Val substitutions in the two proteins were consistent with differences in hydrophobicity of Val and Ile and negligible changes in packing (van der Waals) interactions. The benefit of increased hydrophobicity of the core increased with temperature, with maximal effect around 116 degrees C. Increased hydrophobicity of the core achieved not only an increase in the free energy of unfolding, but also a lateral shift of the temperature of maximal stability to higher temperature. 相似文献
76.
The "desulfo-inhibited" Mo(V) center of bovine milk xanthine oxidase has been investigated by electron-nuclear double resonance spectroscopy. Comparison of spectral data obtained from samples prepared with [1H4]ethylene glycol and with [2H4]ethylene glycol allowed assignment of proton resonance lines due to the methylene protons of the coordinated ethylene glycol (AH = 3.6 MHz). Deuterium resonance lines were observed with the deuterated sample (AD = 0.4 MHz). No spectral evidence was obtained for any weakly coupled nitrogen nuclei to the Mo center under a variety of conditions. Dissolution of the sample in D2O had little effect on the resonance lines centered about the proton Zeeman frequency, which shows they are not due to exchangeable protons and suggests the Mo center does not have contact with bulk solvent. A deuterium delta m = +/- 2 "forbidden" transition is observed at high radio-frequency power levels, which suggests either an exchangeable proton on a Mo ligand or a coordinated solvent. Weakly coupled, nonexchangeable proton lines are observed about the free proton frequency, which exhibit properties characteristic of alpha-protons. A number of arguments are presented to support the proposal that these protons originate from the C(1') and C(2') positions on the side chain of the molybdopterin cofactor. 相似文献
77.
Difference absorption spectroscopy as a function of pH is described as a probe to determine the pKa values of the 8 alpha-imidazole substituent in flavoenzymes containing 8 alpha-histidylflavin coenzymes. Reversible absorption difference spectra are observed in the pH range 5.5 to 8.5 when synthetic 8 alpha-imidazolyl-FMN is bound to the apoflavodoxins from Azotobacter vinelandii and from Clostridium pasterianum. The observed spectral perturbations of these two flavodoxin complexes follow a single proton ionization dependence with respective pKa values of 6.7 and 6.8. No pH-induced spectral perturbations were observed when 8 alpha-(N-CH3)-imidazolium FMN was bound to either flavodoxin. Similar approaches are described to determine the 8 alpha-imidazolyl pKa values of the 8 alpha-histidyl-FAD coenzyme of the cholesterol oxidases from Schizophyllum commune and from Gleocystidium chrysocreas. Previous work has shown the former enzyme contains an 8 alpha-N1-histidyl-FAD (W. C. Kenney et al. (1979) J. Biol. Chem. 254, 4689-4690) while experiments reported here show the latter enzyme also contains one 8 alpha-N1-histidyl-FAD per mole of enzyme. The pKa value for the 8 alpha-imidazole substituent on the flavin of S. commune cholesterol oxidase is 5.4 while that determined for the G. chrysocreas enzyme is 6.2. These results demonstrate that the pKa of the 8 alpha-imidazole substituent can be determined in enzymes containing an 8 alpha-histidylflavin, provided that the enzyme is stable in the pH range required to observe ionization. Furthermore it is shown this the pKa value can differ even on comparison of enzymes from different sources that catalyze the same reaction. 相似文献
78.
Astrotactin: a novel neuronal cell surface antigen that mediates neuron- astroglial interactions in cerebellar microcultures 总被引:4,自引:1,他引:4 下载免费PDF全文
A microculture system for mouse cerebellar cells has been used to identify an immune activity, raised in rabbits against postnatal cerebellar cells, that blocks neuron-glial interactions in vitro. In the presence of blocking antibodies, stable neuron-glial contacts did not form and neuronal induction of glial process outgrowth did not occur. Subsequently, neurons were randomly arranged in the cultures rather than organized along the arms of astroglia. We have named the immune activity that blocks neuron-astroglial interactions anti-astrotactin. Partial purification of the anti-astrotactin blocking antibodies was obtained by cellular absorption with PC12 cells, a clonal cell line which expresses both the N-CAM and NILE (Ng-CAM, L1) glycoproteins. Subsequent absorption with purified cerebellar granule cells, but not with astroglial cells, removed the blocking activity, suggesting that the antigen(s) bound by blocking antibodies are neuronal. Immunoprecipitation of [35S]methionine- or [3H]fucose-radiolabeled Triton extracts of early postnatal cerebellar cells showed that the unabsorbed antiserum recognized a large number of proteins. Among these were bands with apparent molecular masses of N-CAM (180 and 140 kD) and NILE (230 kD). After absorption of the immune serum with PC12 cells, the number of bands recognized by the antiserum was reduced to a prominent band at 100 kD and a diffuse smear of material between 80 and 90 kD. The prominent band at 100 kD was removed by subsequent absorption of the immune serum with granule cells, a step which removed the blocking activity in the cerebellar microculture assay. Further evidence suggests that the astrotactin activity is missing or defective on granule cells from the neurological mutant mouse weaver, an animal that suffers a failure of glial-guided neuronal migration. When anti-astrotactin Fab fragments were pre-absorbed with weaver cerebellar neurons and then tested in the functional assay of neuron-glial interactions, the immune blocking activity was not removed. In contrast, wild-type cerebellar neurons removed the anti-astrotactin blocking activity under the same conditions. Subsequently, when [3H]fucose-radiolabeled Triton extracts of weaver and normal cells were immunoprecipitated with whole or PC12-absorbed anti-astrotactin antiserum, the intensity of the band at 100 kD was reduced by 95% in weaver cells. 相似文献
79.
This study was conducted to determine the effect of thyroid hormone on opiate receptor ligand-binding and pain sensitivity. Specific opiate receptor-binding was performed on brain homogenates of Swiss-Webster mice. There was a significant increase in 3H-naloxone-binding in thyroxine-fed subjects (hyperthyroid). Scatchard analysis revealed that the number of opiate receptors was increased in hyperthyroid mice (Bmax = 0.238 nM for hyperthyroid samples vs. 0.174 nM for controls). Binding affinity was unaffected (Kd = 1.54 nM for hyperthyroid and 1.58 nM for control samples). When mice were subjected to hotplate stimulation, the hyperthyroid mice were noted to be more sensitive as judged by pain aversion response latencies which were half that of control animals. After morphine administration, the hyperthyroid animals demonstrated a shorter duration of analgesia. These findings demonstrate that thyroxine increases opiate receptor number and native pain sensitivity but decreases the duration of analgesia from morphine. 相似文献
80.
A model of the structure of the 22 amino acid residue gastrointestinal peptide hormone motilin in 30% hexafluoro-2-propanol has been obtained by using distance constraints obtained from two-dimensional nuclear Overhauser enhancements. A set of initial structures have been generated by using the distance geometry program DIANA, and 10 of these structures have been refined by using restrained molecular dynamics (AMBER). The resulting structures are virtually indistinguishable in terms of constraint violations and energies and display less than 0.5-A root mean square deviations (RMSD) of the backbone atom positions from Tyr7 to Lys20. A comparison of back-calculated and experimental NOE intensities indicates that RMSD's are not the best indicators of the goodness of fit or of the precision with which the structure is defined. The structure was further refined by fitting the experimental NOE data using an iterative full relaxation matrix analysis. The mean error between the observed and calculated backbone NOE intensities for the final refined structure was 0.23 for the full length of the molecule, 0.18 for the region from Glu9 to Lys20, and 0.29 for the region from Phe1 to Gly8. R factors for the same regions were 0.27, 0.19, and 0.43, respectively. All of the NOE-determined structures consistently display an alpha-helix which extends from Glu9 to Lys20. Considerable lack of definition of structure exists at the amino and carboxyl ends of the molecule and also in the vicinity of Thr6-Tyr7-Gly8. A tendency to form a wide turn appears to exist over the sequence Pro3-Ile4-Phe5-Thr6, but the structure in this region is not well defined by the NOE data. 相似文献