2D3U

X-ray crystal structure of hepatitis C virus RNA dependent RNA polymerase in complex with non-nucleoside analogue inhibitor

2D3U の概要

• エントリーDOI: 10.2210/pdb2d3u/pdb
• 関連するPDBエントリー: 2D3Z 2D41
• 分子名称: polyprotein, 5-(4-CYANOPHENYL)-3-{[(2-METHYLPHENYL)SULFONYL]AMINO}THIOPHENE-2-CARBOXYLIC ACID (3 entities in total)
• 機能のキーワード: hepatitis c virus, rna-dependent rna polymerase, enzyme inhibition, transferase
• 由来する生物種: Hepatitis C virus
• 細胞内の位置: Virion : Q99AU2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 127346.05

構造登録者

Biswal, B.K.,Wang, M.,Cherney, M.M.,Chan, L.,Yannopoulos, C.G.,Bilimoria, D.,Bedard, J.,James, M.N.G. (登録日: 2005-10-02, 公開日: 2006-08-01, 最終更新日: 2024-11-13)

主引用文献

Biswal, B.K.,Wang, M.,Cherney, M.M.,Chan, L.,Yannopoulos, C.G.,Bilimoria, D.,Bedard, J.,James, M.N.G.
Non-nucleoside Inhibitors Binding to Hepatitis C Virus NS5B Polymerase Reveal a Novel Mechanism of Inhibition
J.Mol.Biol., 361:33-45, 2006

PubMed Abstract: The RNA-dependent RNA polymerase (NS5B) from hepatitis C virus (HCV) is a key enzyme in HCV replication. NS5B is a major target for the development of antiviral compounds directed against HCV. Here we present the structures of three thiophene-based non-nucleoside inhibitors (NNIs) bound non-covalently to NS5B. Each of the inhibitors binds to NS5B non-competitively to a common binding site in the "thumb" domain that is approximately 35 Angstroms from the polymerase active site located in the "palm" domain. The three compounds exhibit IC(50) values in the range of 270 nM to 307 nM and have common binding features that result in relatively large conformational changes of residues that interact directly with the inhibitors as well as for other residues adjacent to the binding site. Detailed comparisons of the unbound NS5B structure with those having the bound inhibitors present show that residues Pro495 to Arg505 (the N terminus of the "T" helix) exhibit some of the largest changes. It has been reported that Pro495, Pro496, Val499 and Arg503 are part of the guanosine triphosphate (GTP) specific allosteric binding site located in close proximity to our binding site. It has also been reported that the introduction of mutations to key residues in this region (i.e. Val499Gly) ablate in vivo sub-genomic HCV RNA replication. The details of NS5B polymerase/inhibitor binding interactions coupled with the observed induced conformational changes provide new insights into the design of novel NNIs of HCV.

PubMed: 16828488
DOI: 10.1016/j.jmb.2006.05.074

実験手法

X-RAY DIFFRACTION (2 Å)