2oin

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Revision as of 08:42, 23 January 2008

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spinqualitylabelsall models 2oin, resolution 2.500Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

crystal structure of HCV NS3-4A R155K muntant

Overview

Telaprevir (VX-950) is a highly selective, potent inhibitor of the, hepatitis C virus (HCV) NS3.4A serine protease. It has demonstrated strong, antiviral activity in patients chronically infected with genotype 1 HCV, when dosed alone or in combination with peginterferon alfa-2a., Substitutions of Arg(155) of the HCV NS3 protease domain have been, previously detected in HCV isolates from some patients during telaprevir, dosing. In this study, Arg(155) was replaced with various residues in, genotype 1a protease domain proteins and in genotype 1b HCV subgenomic, replicons. Characterization of both the purified enzymes and reconstituted, replicon cells demonstrated that substitutions of Arg(155) with these, residues conferred low level resistance to telaprevir (<25-fold). An x-ray, structure of genotype 1a HCV protease domain with the R155K mutation, in a, complex with an NS4A co-factor peptide, was determined at a resolution of, 2.5A. The crystal structure of the R155K protease is essentially identical, to that of the wild-type apoenzyme (Protein Data Bank code 1A1R) except, for the side chain of mutated residue 155. Telaprevir was docked into the, x-ray structure of the R155K protease, and modeling analysis suggests that, the P2 group of telaprevir loses several hydrophobic contacts with the, Lys(155) side chain. It was demonstrated that replicon cells containing, substitutions at NS3 protease residue 155 remain fully sensitive to, interferon alpha or ribavirin. Finally, these variant replicons were shown, to have reduced replication capacity compared with the wild-type HCV, replicon in cells.

About this Structure

2OIN is a Single protein structure of sequence from Hepatitis c virus with as ligand. Full crystallographic information is available from OCA.

Reference

Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon alpha., Zhou Y, Muh U, Hanzelka BL, Bartels DJ, Wei Y, Rao BG, Brennan DL, Tigges AM, Swenson L, Kwong AD, Lin C, J Biol Chem. 2007 Aug 3;282(31):22619-28. Epub 2007 Jun 6. PMID:17556358

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