4B73

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

Summary for 4B73

• Entry DOI: 10.2210/pdb4b73/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 4B6F 4B71 4B74 4B75 4B76 8OHM
• Descriptor: NON-STRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3, (2S)-4-amino-N-[(1R)-1-(4-chloro-2-fluoro-3-phenoxyphenyl)propyl]-4-oxobutan-2-aminium (3 entities in total)
• Functional Keywords: hydrolase, helicase-protease, allosteric pocket, fusion protein
• Biological source: HEPATITIS C VIRUS (ISOLATE BK)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26663
• Total number of polymer chains: 2
• Total formula weight: 142470.48

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: 2012-08-16, 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 (2.5 Å)