2oin

crystal structure of HCV NS3-4A R155K muntant

spinqualitylabelsall models 2oin, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2oin is a 4 chain structure with sequence from Hepatitis c virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ZN Gene: NS3 (Hepatitis C virus) Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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