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911.
Anil K. Mantha Indu R. Chandrashekar Najma Z. Baquer Sudha M. Cowsik 《Journal of biomolecular structure & dynamics》2013,31(2):137-147
Abstract Neurokinin B (NKB), a decapeptide of mammalian origin exhibits a variety of biological activities such as regulatory functions in reproduction, pre-eclampsia and neuroprotection in Alzheimer's disease. In order to gain insight into structure-function relationship, three- dimensional structure of NKB has been investigated using CD spectropolarimetry and two-dimensional proton nuclear magnetic resonance (2D 1H-NMR) spectroscopy in aqueous and membrane mimetic solvents. Unambiguous NMR assignments of resonances have been made with the aid of correlation spectroscopy (DQF-COSY and TOCSY) experiments and Nuclear Overhauser Effect Spectroscopy (NOESY) experiments. Distance constraints obtained from the NMR data have been used to generate a family of structures, which have been refined using restrained energy minimization and dynamics. Our data show that a helical structure is induced in NKB, in presence of perdeuterated dodecyl phosphocholine (DPC) micelles, a membrane model system. Further, the conformation adopted by NKB in presence of DPC micelles represents a structural motif typical of neurokinin-3 selective agonists. 相似文献
912.
Bradley Rimmert Salwa Sabet Edward Ackad 《Journal of biomolecular structure & dynamics》2013,31(6):950-958
Egypt has the highest prevalence of hepatitis C virus (HCV) infection worldwide with a frequency of 15%. More than 90% of these infections are due to genotype 4, and the subtype 4a (HCV-4a) predominates. Moreover, due to the increased mobility of people, HCV-4a has recently spread to several European countries. The protease domain of the HCV nonstructural protein 3 (NS3) has been targeted for inhibition by several drugs. This approach has had marked success in inhibiting genotype 1 (HCV-1), the predominant genotype in the USA, Europe, and Japan. However, HCV-4a was found to resist inhibition by a number of these drugs, and little progress has been made to understand the structural basis of its drug resistivity. As a step forward, we sequenced the NS3 HCV-4a protease gene (strain ED43) and subsequently built a 3D structural model threaded through a template crystal structure of HCV-1b NS3 protease. The model protease, HCV-4a, shares 83% sequence identity with the template protease, HCV-1b, and has nearly identical rigid structural features. Molecular dynamics simulations predict similar overall dynamics of the two proteases. However, local dynamics and 4D analysis of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-4a NS3 protease. These results suggest that the divergent dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug resistivity seen in HCV-4a. 相似文献
913.
Yvan Boulanger Louis Sené;cal Gilles Sauvé 《Journal of biomolecular structure & dynamics》2013,31(4):421-428
Abstract The structure of acetyl-pepstatin has been investigated in solution by two-dimensional NMR spectroscopy and molecular modeling. The analysis of DQFCOSY, TOCSY and NOESY spectra lead to a full assignment of the NMR signals both in DMSO-d6 and in TFE-d3:H2O 1:1. Interproton distances, dihedral angles and exchange regimes of NH or OH protons were derived from ROESY connectivities, coupling constants and temperature dependences of the chemical shifts, respectively. Molecular modeling using the NMR distance and dihedral angle constraints obtained in DMSO-d6 yielded a model showing a well-defined structure for the N-terminal segment Ac-1 to Sta-4, but a flexible structure for the C-terminal segment. The structure was less defined in TFE-d3:H2O 1:1 and 13C T1 measurements are indicative of higher mobility. Comparison of the NMR-determined solution structure of acetyl-pepstatin with its crystal structure when bound to HIV-1 protease shows that the conformation is more extended in the complex as a result of intermolecular interactions. 相似文献
914.
N.G. Dolinnaya A.V. Yuminova V.A. Spiridonova A.M. Arutyunyan A.M. Kopylov 《Journal of biomolecular structure & dynamics》2013,31(5):524-531
A number of thrombin-binding DNA aptamers have been developed during recent years. So far the structure of just a single one, 15-mer thrombin-binding aptamer (15TBA), has been solved as G-quadruplex. Structures of others, showing variable anticoagulation activities, are still not known yet. In this paper, we applied the circular dichroism and UV spectroscopy to characterize the temperature unfolding and conformational features of 31-mer thrombin-binding aptamer (31TBA), whose sequence has a potential to form G-quadruplex and duplex domains. Both structural domains were monitored independently in 31TBA and in several control oligonucleotides unable to form either the duplex region or the G-quadruplex region. The major findings are as follows: (1) both duplex and G-quadruplex domains coexist in intramolecular structure of 31TBA, (2) the formation of duplex domain does not change the fold of G-quadruplex, which is very similar to that of 15TBA, and (3) the whole 31TBA structure disrupts if either of two domains is not formed: the absence of duplex structure in 31TBA abolishes G-quadruplex, and vice versa, the lack of G-quadruplex folding results in disallowing the duplex domain. 相似文献
915.
Yeva B. Dalyan Samvel G. Haroutiunian Gayane V. Ananyan Volodya I. Vardanyan Dmitri Y. Lando Valeri N. Madakyan 《Journal of biomolecular structure & dynamics》2013,31(5):677-687
Abstract Interactions of meso-tetra-(4-N-oxyethylpyridyl) porphyrin (TOEPyP(4)), its 3-N analog (TOEPyP(3)) and their Co, Cu, Ni, Zn metallocomplexes with duplex DNA have been investigated by uv/visible absorbance and circular dichrosim spectroscopies. Results reveal the interactions of these complexes with duplex DNA are of two types. (1) External binding of duplex DNA by metalloporphyrins containing Zn and Co, and (2) Binding of duplex DNA both externally and internally (by intercalation) by porphyrins not containing metals, and metalloporphyrins containing Cu and Ni. Results indicate that (4N-oxyethylpyridyl) porphyrins intercalate more preferably in the structure of duplex DNA and have weaker external binding than 3N-porphyrins. 相似文献
916.
Alexei N. Nekrasov Alexei A. Zinchenko 《Journal of biomolecular structure & dynamics》2013,31(5):553-561
Abstract The novel method allowing identification of protein structure elements responsible for catalytic activity manifestation is proposed. Structural organization of various hydrolases was studied using the ANIS (ANalysis of Informational Structure) method. ANIS allows to reveal a hierarchy of the ELements of Information Structure (ELIS) using protein amino acid sequence. The ELIS corresponds to the variable length sites with an increased density of structural information. The amino acid residues forming the enzyme catalytic site were shown to belong to the different top-ranking ELIS located in the contact area of the corresponding spatial structure clusters. In the protein spatial structure catalytic sites are located in the area of contact between fragments of polypeptide chain (structural blocs) allocation to the different top-ranking ELIS. According to our results we concluded that structural blocks corresponding to top-ranking ELIS are crucial for protein functioning. Such regions are structurally independent, and their determinate mobility relative to each other is vital for an efficient enzymatic reaction to occur. 相似文献
917.
Hugo M. Martinez Jacob V. Maizel Jr Bruce A. Shapiro 《Journal of biomolecular structure & dynamics》2013,31(6):669-683
Abstract Using primary and secondary structure information of an RNA molecule, the program RNA2D3D automatically and rapidly produces a first-order approximation of a 3-dimensional conformation consistent with this information. Applicable to structures of arbitrary branching complexity and pseudoknot content, it features efficient interactive graphical editing for the removal of any overlaps introduced by the initial generating procedure and for making conformational changes favorable to targeted features and subsequent refinement. With emphasis on fast exploration of alternative 3D conformations, one may interactively add or delete base-pairs, adjacent stems can be coaxially stacked or unstacked, single strands can be shaped to accommodate special constraints, and arbitrary subsets can be defined and manipulated as rigid bodies. Compaction, whereby base stacking within stems is optimally extended into connecting single strands, is also available as a means of strategically making the structures more compact and revealing folding motifs. Subsequent refinement of the first-order approximation, of modifications, and for the imposing of tertiary constraints is assisted with standard energy refinement techniques. Previously determined coordinates for any part of the molecule are readily incorporated, and any part of the modeled structure can be output as a PDB or XYZ file. Illustrative applications in the areas of ribozymes, viral kissing loops, viral internal ribosome entry sites, and nanobiology are presented. 相似文献
918.
In this study, by applying a combined approach of NMR measurements and molecular modelling, the conformations and the interactions with membrane-like environment of five arginine vasopressin (AVP) or oxytocin (OT) analogues modified with Cα-disubstituted cis-1-amino-4-phenylcyclohexane-1-carboxylic acid in position 2 have been determined. In addition, the AVP analogues were prepared in N-acylated forms with various bulky acyl groups. All of the peptides studied interacted with the mixed dodecylphosphocholine:sodium dodecyl sulphate micelle, providing a model of biological membrane. A different polarities of the AVP- and OT-like peptides resulted in their different position relative to the micelle surface. Thus, the arrangement of the former was nearly perpendicular, whereas the latter was rather parallel to the micelle's surface. Moreover, the results of our studies have shown that the binding sites for antagonists may be overlapped with that for agonists, as well as it may be quite different. Nevertheless, the aromatic–aromatic contacts represent the most important interactions for antagonists, whereas the hydrophilic interactions seem to be crucial for agonists. 相似文献
919.
Alexander M. Andrianov Yuri V. Kornoushenko Ivan V. Anishchenko Vladimir F. Eremin Alexander V. Tuzikov 《Journal of biomolecular structure & dynamics》2013,31(7):665-683
The V3 loop on gp120 from human immunodeficiency virus type 1 (HIV-1) is a focus of many research groups involved in anti-AIDS drug development because this region of the protein is a principal target for neutralizing antibodies and a major determinant for cell tropism and syncytium formation. In this study, the nucleotide sequences of the env gene region coding the V3 loop were determined by DNA sequencing methods for four novel HIV-1 strains that circulate in the countries of Eastern Europe, such as Russia, Belarus, Ukraine, etc. Based on the empirical data obtained, the 3D structures of the V3 loops associated with these viral modifications were generated by computer modeling and then compared to discover similarities in the spatial arrangement of this functionally important site of gp120. Despite the HIV-1 genetic variety, several regions of the V3 loop that contain residues critical for cell tropism were shown to be structurally invariant, which may explain its exceptional role in a co-receptor usage. These data together with those on the biological activity of the V3 individual residues clearly show that these conserved structural motifs of gp120 represent potential HIV-1 weak points most suitable for therapeutic intervention. 相似文献
920.
Karunakar Tanneeru Ashok Raja Balla 《Journal of biomolecular structure & dynamics》2013,31(8):1710-1719
Human male germ cell-associated kinase (hMAK) is an androgen-inducible gene in prostate epithelial cells, and it acts as a coactivator of androgen receptor signaling in prostate cancer. The 3D structure of the hMAK kinase was modeled based on the crystal structure of CDK2 kinase using comparative modeling methods, and the ATP-binding site was characterized. We have collected five inhibitors of hMAK from the literature and docked into the ATP-binding site of the kinase domain. Solvated interaction energies (SIE) of inhibitor binding are calculated from the molecular dynamics simulations trajectories of protein–inhibitor complexes. The contribution from each active site residue in hMAK toward inhibitor binding revealed the nature and extent of interactions between inhibitors and individual residues. The main chain atoms of Met79 invariably form hydrogen bonds with all five inhibitors. The amino acids Leu7, Val15, and Leu129 stabilize the inhibitors via CH–pi interactions. The Asp140 in the active site and Glu77 in hinge region show characteristic hydrogen bonding interactions with inhibitors. From SIE, the residue-wise interactions revealed the nature of non-bonding contacts and modifications required to increase the inhibitor activity. Our work provides 3D model structure of hMAK and molecular basis for the mechanisms of hMAK inhibition at atomic level that aid in designing new potent inhibitors. 相似文献