2OIN
crystal structure of HCV NS3-4A R155K mutant
Summary for 2OIN
| Entry DOI | 10.2210/pdb2oin/pdb |
| Descriptor | Polyprotein, NS4A peptide, ZINC ION, ... (4 entities in total) |
| Functional Keywords | hcv, protease, ns3-4a, r155k mutant, hydrolase |
| Biological source | Hepatitis C virus More |
| Total number of polymer chains | 4 |
| Total formula weight | 46696.39 |
| Authors | |
| Primary citation | Zhou, Y.,Muh, U.,Hanzelka, B.L.,Bartels, D.J.,Wei, Y.,Rao, B.G.,Brennan, D.L.,Tigges, A.M.,Swenson, L.,Kwong, A.D.,Lin, C. Phenotypic and structural analyses of hepatitis C virus NS3 protease Arg155 variants: sensitivity to telaprevir (VX-950) and interferon alpha. J.Biol.Chem., 282:22619-22628, 2007 Cited by PubMed Abstract: 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. PubMed: 17556358DOI: 10.1074/jbc.M610207200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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