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Originally published In Press as doi:10.1074/jbc.M209397200 on December 30, 2002

J. Biol. Chem., Vol. 278, Issue 11, 9489-9495, March 14, 2003
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Non-nucleoside Analogue Inhibitors Bind to an Allosteric Site on HCV NS5B Polymerase
CRYSTAL STRUCTURES AND MECHANISM OF INHIBITION*

Meitian WangDagger , Kenneth K.-S. NgDagger §, Maia M. CherneyDagger , Laval Chan, Constantin G. Yannopoulos, Jean Bedard, Nicolas Morin, Nghe Nguyen-Ba, Moulay H. Alaoui-Ismaili, Richard C. Bethell, and Michael N. G. JamesDagger ||

From the Dagger  Canadian Institutes for Health Research Group in Protein Structure and Function, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada and  Shire BioChem Inc., Laval, Quebec H7V 4A7, Canada

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 Å resolution. These noncompetitive inhibitors bind to the same site on the protein, ~35 Å 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 Ser476 and Tyr477 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.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Support by a Canadian Institutes for Health Research Senior Research Fellowship and funds from the Alberta Heritage Foundation for Medical Research.

|| Canada Research Chair in Protein Structure and Function. To whom correspondence should be addressed. Tel.: 780-492-4550; Fax: 780-492-0886; E-mail: Michael.james@ualberta.ca.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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