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

Here we report the discovery of a highly conserved novel 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...

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Autores principales: Saalau-Bethell, Susanne M., Woodhead, Andrew J., Chessari, Gianni, Carr, Maria G., Coyle, Joseph, Graham, Brent, Hiscock, Steven D., Murray, Christopher W., Pathuri, Puja, Rich, Sharna J., Richardson, Caroline J., Williams, Pamela A., Jhoti, Harren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480716/
https://www.ncbi.nlm.nih.gov/pubmed/23023261
http://dx.doi.org/10.1038/nchembio.1081
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author Saalau-Bethell, Susanne M.
Woodhead, Andrew J.
Chessari, Gianni
Carr, Maria G.
Coyle, Joseph
Graham, Brent
Hiscock, Steven D.
Murray, Christopher W.
Pathuri, Puja
Rich, Sharna J.
Richardson, Caroline J.
Williams, Pamela A.
Jhoti, Harren
author_facet Saalau-Bethell, Susanne M.
Woodhead, Andrew J.
Chessari, Gianni
Carr, Maria G.
Coyle, Joseph
Graham, Brent
Hiscock, Steven D.
Murray, Christopher W.
Pathuri, Puja
Rich, Sharna J.
Richardson, Caroline J.
Williams, Pamela A.
Jhoti, Harren
author_sort Saalau-Bethell, Susanne M.
collection PubMed
description Here we report the discovery of a highly conserved novel 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 stabilising an inactive conformation and thus represent a new class of direct acting antiviral agents.
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spelling pubmed-34807162013-05-01 Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function Saalau-Bethell, Susanne M. Woodhead, Andrew J. Chessari, Gianni Carr, Maria G. Coyle, Joseph Graham, Brent Hiscock, Steven D. Murray, Christopher W. Pathuri, Puja Rich, Sharna J. Richardson, Caroline J. Williams, Pamela A. Jhoti, Harren Nat Chem Biol Article Here we report the discovery of a highly conserved novel 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 stabilising an inactive conformation and thus represent a new class of direct acting antiviral agents. 2012-09-30 2012-11 /pmc/articles/PMC3480716/ /pubmed/23023261 http://dx.doi.org/10.1038/nchembio.1081 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Saalau-Bethell, Susanne M.
Woodhead, Andrew J.
Chessari, Gianni
Carr, Maria G.
Coyle, Joseph
Graham, Brent
Hiscock, Steven D.
Murray, Christopher W.
Pathuri, Puja
Rich, Sharna J.
Richardson, Caroline J.
Williams, Pamela A.
Jhoti, Harren
Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function
title Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function
title_full Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function
title_fullStr Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function
title_full_unstemmed Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function
title_short Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function
title_sort discovery of an allosteric mechanism for the regulation of hcv ns3 protein function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3480716/
https://www.ncbi.nlm.nih.gov/pubmed/23023261
http://dx.doi.org/10.1038/nchembio.1081
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