Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition

X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNA-dependent RNA polymerase have been determined to 2.0 and 2.9 A resolution. These noncompetitive inhibitors bind to the same site on the protein, approximately 35 A from the active site. The common...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-03, Vol.278 (11), p.9489-9495
Main Authors: Wang, Meitian, Ng, Kenneth K-S, Cherney, Maia M, Chan, Laval, Yannopoulos, Constantin G, Bedard, Jean, Morin, Nicolas, Nguyen-Ba, Nghe, Alaoui-Ismaili, Moulay H, Bethell, Richard C, James, Michael N G
Format: Article
Language:English
Subjects:
Allosteric Site
Amino Acid Sequence
Binding Sites
Binding, Competitive
Crystallography, X-Ray
Dose-Response Relationship, Drug
Hydrogen Bonding
Inhibitory Concentration 50
Models, Chemical
Models, Molecular
Molecular Sequence Data
Nitrogen
Nucleosides - chemistry
Oxygen
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Recombinant Proteins - chemistry
Serine - chemistry
Tyrosine - chemistry
Viral Nonstructural Proteins - genetics
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Summary:X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNA-dependent RNA polymerase have been determined to 2.0 and 2.9 A resolution. These noncompetitive inhibitors bind to the same site on the protein, approximately 35 A from the active site. The common features of binding include a large hydrophobic region and two hydrogen bonds between both oxygen atoms of a carboxylate group on the inhibitor and two main chain amide nitrogen atoms of Ser(476) and Tyr(477) on NS5B. The inhibitor-binding site lies at the base of the thumb domain, near its interface with the C-terminal extension of NS5B. The location of this inhibitor-binding site suggests that the binding of these inhibitors interferes with a conformational change essential for the activity of the polymerase.
ISSN:0021-9258
DOI:10.1074/jbc.M209397200