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      Comparison of Structural Architecture of HCV NS3 Genotype 1 versus Pakistani Genotype 3a

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          Abstract

          This study described the structural characterization of Pakistani HCV NS3 GT3a in parallel with genotypes 1a and 1b NS3. We investigated the role of amino acids and their interaction patterns in different HCV genotypes by crystallographic modeling. Different softwares were used to study the interaction pattern, for example, CLCBIO sequence viewer, MODELLER, NMRCLUST, ERRAT score, and MODELLER. Sixty models were produced and clustered into groups and the best model of PK-NCVI/Pk3a NS3 was selected and studied further to check the variability with other HCV NS3 genotypes. This study will help in future to understand the structural architecture of HCV genome variability and to further define the conserved targets for antiviral agents.

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          Most cited references37

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          An automated approach for clustering an ensemble of NMR-derived protein structures into conformationally related subfamilies.

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            Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.

            An estimated 1% of the global human population is infected by hepatitis C viruses (HCVs), and there are no broadly effective treatments for the debilitating progression of chronic hepatitis C. A serine protease located within the HCV NS3 protein processes the viral polyprotein at four specific sites and is considered essential for replication. Thus, it emerges as an attractive target for drug design. We report here the 2.5 angstrom resolution X-ray crystal structure of the NS3 protease domain complexed with a synthetic NS4A activator peptide. The protease has a chymotrypsin-like fold and features a tetrahedrally coordinated metal ion distal to the active site. The NS4A peptide intercalates within a beta sheet of the enzyme core.
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              Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism.

              A virally encoded superfamily-2 (SF2) helicase (NS3h) is essential for the replication of hepatitis C virus, a leading cause of liver disease worldwide. Efforts to elucidate the function of NS3h and to develop inhibitors against it, however, have been hampered by limited understanding of its molecular mechanism. Here we show x-ray crystal structures for a set of NS3h complexes, including ground-state and transition-state ternary complexes captured with ATP mimics (ADP.BeF(3) and ). These structures provide, for the first time, three conformational snapshots demonstrating the molecular basis of action for a SF2 helicase. Upon nucleotide binding, overall domain rotation along with structural transitions in motif V and the bound DNA leads to the release of one base from the substrate base-stacking row and the loss of several interactions between NS3h and the 3' DNA segment. As nucleotide hydrolysis proceeds into the transition state, stretching of a "spring" helix and another overall conformational change couples rearrangement of the (d)NTPase active site to additional hydrogen-bonding between NS3h and DNA. Together with biochemistry, these results demonstrate a "ratchet" mechanism involved in the unidirectional translocation and define the step size of NS3h as one base per nucleotide hydrolysis cycle. These findings suggest feasible strategies for developing specific inhibitors to block the action of this attractive, yet largely unexplored drug target.
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                Author and article information

                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi Publishing Corporation
                2314-6133
                2314-6141
                2014
                21 October 2014
                : 2014
                : 749254
                Affiliations
                1IQ Institute of Infection and Immunity, P.O. Box 54000, Lahore, Punjab, Pakistan
                2King Fahd Medical Research Center, King Abdul Aziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
                3Center of Excellence in Genomic Medicine, King Abdul Aziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
                Author notes

                Academic Editor: Sherry L. Mowbray

                Author information
                http://orcid.org/0000-0001-7509-8530
                http://orcid.org/0000-0002-1736-181X
                http://orcid.org/0000-0003-4334-0585
                Article
                10.1155/2014/749254
                4221965
                3250b32d-07d7-4a15-a2d8-7c31bea9f013
                Copyright © 2014 Kaneez Fatima et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 March 2014
                : 10 August 2014
                : 19 August 2014
                Categories
                Research Article

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