3VQS
Crystal structure of HCV NS5B RNA polymerase with a novel piperazine inhibitor
Summary for 3VQS
| Entry DOI | 10.2210/pdb3vqs/pdb |
| Related | 1QUV 2DXS |
| Descriptor | RNA-directed RNA polymerase, (2R)-4-(5-cyclopropyl[1,3]thiazolo[4,5-d]pyrimidin-2-yl)-N-[3-fluoro-4-(trifluoromethoxy)benzyl]-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine-2-carboxamide, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | rna-dependent rna polymerase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Hepatitis C virus |
| Total number of polymer chains | 4 |
| Total formula weight | 259879.85 |
| Authors | Adachi, T.,Doi, S.,Ando, I.,Sugimoto, K.,Orita, T.,Nomura, A.,Kamada, M. (deposition date: 2012-03-30, release date: 2012-08-08, Last modification date: 2024-11-20) |
| Primary citation | Ando, I.,Adachi, T.,Ogura, N.,Toyonaga, Y.,Sugimoto, K.,Abe, H.,Kamada, M.,Noguchi, T. Preclinical Characterization of JTK-853, a Novel Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase. Antimicrob.Agents Chemother., 56:4250-4256, 2012 Cited by PubMed Abstract: JTK-853 is a novel piperazine derivative nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase. JTK-853 showed potent inhibitory activity against genotype 1 HCV polymerase, with a 50% inhibitory concentration in the nanomolar range, and showed potent antiviral activity against the genotype 1b replicon, with a 50% effective concentration of 0.035 μM. The presence of human serum at up to 40% had little effect on the antiviral activity of JTK-853. Structure analysis of HCV polymerase with JTK-853 revealed that JTK-853 associates with the palm site and β-hairpin region of HCV polymerase, and JTK-853 showed decreased antiviral activity against HCV replicons bearing the resistance mutations C316Y, M414T, Y452H, and L466V in the palm site region of HCV polymerase. JTK-853 showed an additive combination effect with other DAAs (direct antiviral agents), such as nucleoside polymerase inhibitor, thumb pocket-binding nonnucleoside polymerase inhibitor, NS5A inhibitor, and protease inhibitor. Collectively, these data demonstrate that JTK-853 is a potent and novel nonnucleoside palm site-binding HCV polymerase inhibitor, suggesting JTK-853 as a potentially useful agent in combination with other DAAs for treatment of HCV infections. PubMed: 22615294DOI: 10.1128/AAC.00312-12 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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