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Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function.

ABSTRACT: Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure-guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and thus represent a new class of direct-acting antiviral agents.

SUBMITTER: Saalau-Bethell SM

PROVIDER: S-EPMC3480716 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function.

Saalau-Bethell Susanne M SM Woodhead Andrew J AJ Chessari Gianni G Carr Maria G MG Coyle Joseph J Graham Brent B Hiscock Steven D SD Murray Christopher W CW Pathuri Puja P Rich Sharna J SJ Richardson Caroline J CJ Williams Pamela A PA Jhoti Harren H

Nature chemical biology 20120930 11

Here we report a highly conserved new binding site located at the interface between the protease and helicase domains of the hepatitis C virus (HCV) NS3 protein. Using a chemical lead, identified by fragment screening and structure-guided design, we demonstrate that this site has a regulatory function on the protease activity via an allosteric mechanism. We propose that compounds binding at this allosteric site inhibit the function of the NS3 protein by stabilizing an inactive conformation and t ...[more]

PMID: 23023261

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