4B6F

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

Summary for 4B6F

• Entry DOI: 10.2210/pdb4b6f/pdb
• Related: 1A1Q 1BT7 1C2P 1CSJ 1CU1 1GX5 1GX6 1JXP 1NHU 1NHV 1NS3 1OS5 1QUV 2AWZ 2AX0 2AX1 2BRK 2BRL 2I1R 2JC0 2JC1 2WCX 2WHO 2XWY 4A92 4B6E 8OHM
• Descriptor: NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3, SULFATE ION, (4-phenoxyphenyl)methylazanium, ... (4 entities in total)
• Functional Keywords: hydrolase, helicase-protease, allosteric pocket, fusion protein
• Biological source: HEPATITIS C VIRUS (ISOLATE BK)
• Total number of polymer chains: 2
• Total formula weight: 145525.25

Authors

Saalau-Bethell, S.M.,Woodhead, A.J.,Chessari, G.,Carr, M.G.,Coyle, J.,Graham, B.,Hiscock, S.D.,Murray, C.W.,Pathuri, P.,Rich, S.J.,Richardson, C.J.,Williams, P.A.,Jhoti, H. (deposition date: 2012-08-09, release date: 2012-10-03, Last modification date: 2023-12-20)

Primary citation

Saalau-Bethell, S.M.,Woodhead, A.J.,Chessari, G.,Carr, M.G.,Coyle, J.,Graham, B.,Hiscock, S.D.,Murray, C.W.,Pathuri, P.,Rich, S.J.,Richardson, C.J.,Williams, P.A.,Jhoti, H.
Discovery of an Allosteric Mechanism for the Regulation of Hcv Ns3 Protein Function.
Nat.Chem.Biol., 8:920-, 2012

PubMed 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.

PubMed: 23023261
DOI: 10.1038/NCHEMBIO.1081

Experimental method

X-RAY DIFFRACTION (2.89 Å)