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At least 1,711 records · Page 95Linked to original sources
PubMed1975

Stimulus-response coupling in neurohypophysial peptide target cells.

Recent data on the effects of neurohypophysial peptides at the cellular level are discussed with respect to the two basic processes involved in peptide hormone action--i.e., specific recognition of the information contained in the hormonal molecule and the transformation of this information into a stimulus leading to the final biological response. Four main aspects of this general problem are considered. A. Hormone-Receptor Interaction: Recent contributions in this field concern partial analysis of the three-dimensional conformation of oxytocin and vasopressin moleculal cells of the mammalian kidney. Conformational analysis of oxytocin and vasopressin molecules leads to the conclusion that, in solution, these peptides probably have a compact and highly stabilized three-dimensional configuration. Models have been proposed that provide a valuable clue to the interpretation of structure-activity relationships among natural hormones and many structural analogues. Binding studies with tritiated oxytocin and vasopressin have permitted determination of the kinetic parameters of hormone-receptor interaction in amphibian epithelial cells and mammalian kidney. B. Stimulus Generation: The nature of the primary stimulus generated by hormone-receptor interaction is still unknown. In the epithelial target cells of the amphibian skin and bladder and of the mammalian kidney, one of the first consequences of hormone-receptor interaction is the activation of membrane-bound adenylate cyclase. Analysis of the correlations between hormonal binding and adenylate cyclase activation suggests that activation is a function of receptor occupation rather than of the number of hormonal molecules interacting with the receptor per unit of time. On medullary adenylate cyclase of pig kidney, the relation between receptor occupancy and enzyme activation was found to be complex and nonlinear. The effects of several agents (calcium, nucleotides) on receptor occupancy and adenylate cyclase activation have been described. In mammalian uterus and other smooth muscle target cells, there is no evidence for direct involvement of cyclic AMP in the contractile response to oxytocin and other neurohypophysial peptides.

Adenylyl Cyclases↗
PubMed2004

Synthesis and morphine enhancement activity of N-[5-(2-phenoxyphenyl)-1, 3, 4-oxadiazole-2-yl]-N'-phenylurea derivatives.

The synthesis of N-[5-(2-phenoxyphenyl)-1, 3, 4-oxadiazole-2-yl]-N'-phenylurea derivatives is reported. The structures of these compounds are supported by their IR, (1)H-NMR and mass spectra. Conformational analysis and superimposition of energy minima conformers of these compounds on L-365, 260, a known 3-ureido-1, 4-benzodiazepine CCK-B antagonist, showed that the aromatic rings fell in the same contour. Morphine analgesia enhancement evaluation of the synthesized compounds in comparison with a control group showed that compounds 8a, 8c, 8h-8j, 8l, 8o have significant effects.

Analgesia↗
PubMed1989

Sequence dependence of the B-A conformational transition of DNA.

We have studied, by conformational analysis, the sequence dependence of DNA conformational transition between B- and A-forms. We have considered intramolecular interactions between base pairs, without backbone, to examine their role in the conformational transition between B- and A-forms, and found that base pairs themselves usually have intrinsic conformational preferences for the B- or A-form. Calculation of all ten possible base steps shows that the base combinations, CC (or GG), GC, AT, and TA, have tendencies to assume the A-conformation. Results show that it is particularly easy to slide along the long axis of the base pair for these steps, with AT and CC showing especially flat energies. These calculations show that a preference for the B- or A-conformation depends on the electrostatic energy parameters, in particular, on dielectric and shielding constants; the A-conformation is preferred for low dielectric constant or low shielding. Both the A- and B-conformations are mainly stabilized by electrostatic interactions between favorably juxtaposed atomic charges on base pairs; however, the B-conformation generally has more favorable van der Waals interactions than the A-form. These sequence-dependent conformational preference and environmental effects agree roughly with experimental observations, suggesting that the origin of the conformational polymorphism is attributable to the intrinsic conformational preference of base pairs.

Base Sequence↗
PubMedDate not supplied

On the hydrodynamic analysis of macromolecular conformation.

Hydrodynamics provides a powerful complementary role to the traditional "high resolution" techniques for the investigation of macromolecular conformation, especially in dilute solution, conditions which are generally inaccessible to other structural techniques. This paper describes the state of art of hydrodynamic representations for macromolecular conformation, in terms of (1) simple but straightforward ellipsoid of revolution modelling; (2) general triaxial ellipsoid modelling; (3) hydrodynamic bead modelling; (4) the ability, especially for polydisperse macromolecular systems, to distinguish between various conformation types; (5) analysis of macromolecular flexibility.

Journal Article↗
PubMed2005

Design and synthesis of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles as benzodiazepine receptor agonists.

A series of new 2-substituted-5-(2-benzylthiophenyl)-1,3,4-oxadiazoles was designed and synthesized as anticonvulsant agents. Conformational analysis and superimposition of energy minima conformers of the designed molecules on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at para position of benzylthio moiety had the best anticonvulsant activity. It seems this effect is mediated through benzodiazepine receptors mechanism.

Animals↗
PubMed1998

Design and synthesis of novel conformationally restricted HIV protease inhibitors.

A set of HIV protease inhibitors represented by compound 2 has previously been described. Structural and conformational analysis of this compound suggested that conformational restriction of the P1/P2 portion of the molecule could lead to a novel set of potent protease inhibitors. Thus, probe compounds 3-7 were designed, synthesized, and found to be potent inhibitors of HIV protease.

Anti-HIV Agents↗
PubMed2000

Investigating the role of the geminal dimethyl groups of coenzyme A: synthesis and studies of a didemethyl analogue.

An analogue 2 of coenzyme A (CoA) has been prepared in which the geminal methyl groups are replaced with hydrogens. An NMR titration study was conducted and shifts in frequency of protons in the pantetheine portion of the molecule upon titration of the adenine base were observed as has been previously reported with CoA. These studies indicate that the geminal dimethyl groups are not essential for adoption of a partially folded conformation in solution. Based on 1H-1H coupling constants, the distribution of conformations about the carbon-carbon bonds in the region of the methyl deletion were estimated. The results suggest that the conformer distribution is similar to that of CoA, but with small increases in population of the anti conformers. A simple model compound containing the didemethyl pantoamide moiety was prepared and subjected to similar conformational analysis. The coupling constants and predicted conformer distribution were almost identical to that of the CoA analogue, indicating that the conformer distribution is controlled by local interactions and not influenced by interactions between distant parts of the CoA molecule. The acetyl derivative of 2 was a fairly good substrate for the acetyl-CoA utilizing enzymes carnitine acetyltransferase, chloramphenicol acetyltransferase, and citrate synthase, with 1.3- to 10-fold increased Km values and 2.5- to 11-fold decreases in Vmax. The combined results indicate that the geminal dimethyl groups of CoA have modest effects on function and minimal effects on conformation.

Carnitine O-Acetyltransferase↗
PubMed2003

Design and synthesis of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists.

A series of new 5-substituted analogues of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole and its chlorinated derivatives was designed and prepared. Conformational analysis and superimposition of energy minima conformers of the compounds on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Rotarod and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 5 of 1,2,4-triazole ring especially in chlorinated derivatives had the best effect which was comparable with diazepam.

Animals↗
PubMed2003

A frame shifted disulfide bridged analogue of angiotensin II.

N-(2-Mercaptoethyl)glycine [NMGly] was incorporated into the 3 and 5 positions of angiotensin II and oxidized to give the corresponding cyclized disulfide c[NMGly(3,5)]Ang II. The binding affinity to the angiotensin II receptor (AT(1)) of this conformationally constrained analogue, which is related to the potent Ang II agonist c[Hcy(3,5)]Ang II, was examined. The analogue had no affinity to the AT(1) receptor. Theoretical conformational analysis was performed to compare the conformational characteristics of model compounds of c[Hcy(3,5)]Ang II and the frame shifted analogue c[NMGly(3,5)]Ang II in an attempt to explain the lack of affinity.

Angiotensin II↗
PubMed2003

2D conformationally sampled pharmacophore: a ligand-based pharmacophore to differentiate delta opioid agonists from antagonists.

Pharmacophores are widely used for rational drug design and include those based on receptor binding sites or on known ligands. To date, ligand-based pharmacophores have typically used one or a small number of conformers of known receptor ligands. However, this method does not take into account the inherent dynamic nature of molecules, which sample a wide range of conformations, any of which could be the bound form. In the present study, molecular dynamics (MD) simulations were used as a means to sample the conformational space of ligands to include all accessible conformers at room temperature in the development of a pharmacophore. On the basis of these conformers, probability distributions of selected distances and angles in a series of delta specific opioid ligands were obtained and correlated with agonist versus antagonist activities. Individually, the distributions did not allow for unique agonist and antagonist pharmacophores to be identified. However, by extending the conformational analysis to two dimensions, a 2D conformationally sampled pharmacophore (CSP) for distinguishing delta receptor agonists and antagonists was developed. Application of this model to the compound DPI2505 suggests that it may have agonist activity. It is anticipated that the CSP method, which does not require alignment of compounds during pharmacophore development, will be a useful tool for obtaining structure-function relationships of ligands particularly in systems where the receptor 3D structure is not known.

Computer Simulation↗
PubMed2005

Metal recognition of septapeptides via polypod molecular architecture.

The understanding of the nature of recognition of inorganic materials by proteins is one of the core elements of and has profound implications in biological materials science and engineering. Using combinatorial display methods, a considerable number of short polypeptides have recently been selected with affinity to engineering materials. During these selections, more than several polypeptides are identified with binding specificity to a chosen inorganic material. Understanding the nature of surface recognition of materials by polypeptides is essential for rational design and biomimetic engineering of these inorganic-binding polypeptides for use as linkers, catalyzers, and growth modifiers in nanotechnology and nanobiotechnology. Although there may not be direct homology among the amino acids constituting the polypeptides, their function may come from conserved molecular architecture. Here we study crystallographic surface recognition of platinum metal-binding septapeptides by conformational analysis. We find that the septapeptides conform into certain molecular architectures containing multiple protrusions (polypods) that spatially match with the crystallographic metal surfaces. While the physical recognition may originate from how well the molecular polypods spatially match a given crystallographic surface, the degree of binding may be due to the reactive groups that form the polypods, e.g., charged or polar groups (e.g., hydroxyl and amine). These results are highly consistent with the experimental binding characteristics of the Pt binders with various degrees of affinities.

Binding Sites↗
PubMed2004

Polymorphisms of the equine major histocompatibility complex class II DRA locus.

The full extent of the polymorphism of ELA-DRA in Equidae is not yet known. Given the apparent differences in DRA polymorphisms between Equidae and other species, the aims of this study were to more fully characterize ELA-DRA, determine the extent of gene polymorphism and establish the allele-frequency distribution. An allele reference panel for the second exon of ELA-DRA was established by sequence-based typing of 69 equine DNA samples consisting of various breeds of domestic horse (Equus caballus), together with donkeys (Equus asinus), Grant's zebras (Equus boehmi) and one onager (Equus hemionus). Five of the six previously reported alleles detected using single-strand conformation polymorphism were found: ELA-DRA*0101, ELA-DRA*0201, ELA-DRA*0301, ELA-DRA*0501 (Albright-Fraser DG et al. Polymorphism of DRA among equids. Immunogenetics 1996: 43: 315-7) and ELA-DRA*0601 (GenBank accession number AF5419361). In addition to the previously reported alleles, five novel ELA-DRA alleles were detected within the ELA-DRA allele reference panel. One of these was identified in E. caballus (ELA-DRA*JBH11), one in E. boehmi and E. hemionus (ELA-DRA*JBZ185) and three in E. asinus (ELA-DRA*JBD3, ELA-DRA*JBD17 and ELA-DRA*JBH45). A total of 565 equine DNA samples were screened using reference-strand-mediated conformation analysis, a double-stranded conformation-based mutation detection system that can be used to type existing ELA-DRA alleles and identify new variants. Based on our findings, at least 11 ELA-DRA alleles are now known to exist, and this level of polymorphism at the DRA locus appears to be unique to the genus Equus. Both the previously reported alleles and the new alleles displayed a species-specific distribution.

Amino Acid Sequence↗
PubMed1999

[Mechanism of action of aspartic proteases. IV.Conformational characteristics of a substrate and an inhibitor of rhizopuspepsin ].

On the basis of theoretical conformational analysis of separate peptide fragments, the conformational characteristics of two substrates and a substrate-like inhibitor of aspartic protease rhizopuspepsin were studied. It was shown that the spatial structure of these molecules is described by several families of conformations, the transition between which does not require the overcoming of high energy barriers. It was assumed that the stabilization of beta-structural conformations experimentally observed in inhibitor complexes is due to the greater predisposition of extended structures to the formation of effective intermolecular contacts with amino acid residues of the active site of the enzyme.

Aspartic Acid Endopeptidases↗
PubMed1999

[Mechanism of action of aspartyl proteinases. VI. Nonvalent enzyme-inhibitory and enzyme-substrate complexes of the aspartyl proteinase rhizopus pepsin].

The structure of a complex of rhizopuspepsin, a fungal aspartyl protease, with Pro1-Phe2-His3-Phe4-psi[CH2-NH]-Phe5-Val6, its substrate-like inhibitor, was calculated by theoretical conformational analysis. The search for energetically favorable conformational variants of the ligand structure was based on the fragmental approach using the dynamic library of peptide fragments, which were successively extended in the potential field of the protein. The root-mean-square deviation of atom positions in the calculated and experimental inhibitor conformations was 0.56 A. A similar approach was used to model a noncovalent complex of rhizopuspepsin with Pro1-Phe2-His3-Lys4-Phe5-Val6, its specific substrate. As a result, two isoenergetic structures of the complex with different arrangements of the cleavable peptide group and a nucleophilic water molecule were calculated. The possibility of the achieving each of these conformations during the catalytic act is considered. It is shown that there are no structural prerequisites for the distortion of the cleavable bond in the active site of the enzyme. On the basis of the resulting structural data, the assumption was made that Asp35 may be protonated at a late stage of formation of the tetrahedral intermediate rather than at the basic state of the complex.

Amino Acid Sequence↗
PubMed2004

[Study on the correlation of interleukin-13 polymorphism and susceptibility to chronic obstructive pulmonary disease in Chinese Han population].

OBJECTIVE: To investigate the polymorphism of interleukin (IL)-13 gene in Chinese Han population, and to study the possible association of IL-13 polymorphism and the susceptibility to chronic obstructive pulmonary disease (COPD). METHODS: Using genomic DNA extracted with phenol:chloroform:isoamyl alcohol from the blood of 94 healthy smokers and 88 COPD smokers, three single nucleotide polymorphism (SNP) sites in IL-13 gene marked as 1103C/T, 4257G/A, 4738G/A were determined by polymerase chain reaction/restriction fragment length polymorphism analysis or polymerase chain reaction/single strand conformation analysis. In addition, plasma IL-13 concentration was measured by ELISA on 24 healthy smokers and 24 smokers with chronic obstructive pulmonary disease. RESULTS: (1) To 4257G/A and 4738G/A SNP sites, the genotype frequencies and allele frequencies were not significantly different between healthy smokers and COPD smokers (P > 0.1). (2) To 1103C/T SNP site, relative higher CC genotype frequency and C allele frequency were found in healthy smokers (P < 0.05), also C allele could prevent smokers from chronic obstructive pulmonary disease, with OR 0.56 and 95% confidence interval was 0.34 - 0.91. (3) Plasma IL-13 concentration was not affected by genotype of 4257G/A or 4738G/A SNP sites. However, 1103CC showed for significantly lower IL-13 concentration in plasma (P < 0.05). CONCLUSION: The genotype of IL-13 1103C/T SNP site was associated with the susceptibility to COPD in Chinese Han population and 1103CC accounted for relative lower plasma IL-13 concentration and lower risk for COPD.

Aged↗
PubMedDate not supplied

[Conformation states of thymopentin and its synthetic analogs].

Spatial structures of the biologically active fragment Arg-Lys-Asp-Val-Tyr of tymopoetin (tymopentin) and its synthetic analogs: [Lys1-Arg2]-, [Glu3]- and [Gly3] have been investigated by theoretical conformational analysis. These results indicate that the conformational properties of fragments are represented in aqueous solution by five different backbone forms.

Amino Acid Sequence↗
PubMed1988

[Conformation possibilities of the lipotropic acton of human somatotropin].

Using a semiempirical conformational analysis, a three-dimensional structure and conformational properties of human somatotropin free lipotropical action and fragment 31-44 possessing identical amino acid sequences were investigated. The calculations were performed on the basis of the fragmental analysis, using nonvalent, electrostatic and torsional interactions and hydrogen bonds. The data obtained suggest that these molecules can exist only in several low energy conformations. The conformational possibilities of the free acton molecule and fragment 31-44 differ essentially. The experimental results can be used for the study of structure-function relationships.

Amino Acid Sequence↗
PubMed1999

Identification of human cytomegalovirus variants by analysis of single strand conformation polymorphism and DNA sequencing of the envelope glycoprotein B gene region-distribution frequency in liver transplant recipients.

Single strand conformation polymorphism analysis (SSCP) of PCR-amplified DNA and subsequent DNA sequencing of human cytomegalovirus (HCMV) glycoprotein B (gB) gene were applied to identify known HCMV strains and to detect new virus variants. 61 HCMV PCR positive patients were studied out of a cohort of 410 patients after liver transplantation (LTX). SSCP was able to distinguish between strains Davis, AD169, and Towne, and in addition could identify five new virus variants (Berlin B, C, E, F, and H). Their frequency, gB and gH types were determined. Simultaneous infections with two or three strains or variants, as well as a switch from one virus to another virus were observed during long-term follow-up. No correlation between the occurrence of certain virus strains or gB types and defined clinical manifestations of HCMV infection after LTX was drawn.

Base Sequence↗