4I31

Crystal structure of HCV NS3/NS4A protease complexed with compound 4

Summary for 4I31

• Entry DOI: 10.2210/pdb4i31/pdb
• Descriptor: Genome polyprotein, HCV non-structural protein 4A, SODIUM ION, ... (5 entities in total)
• Functional Keywords: hepatitis c virus, ns3, ns4a, protein-inhibitor complex compound 4, serine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Hepatitis C virus (HCV); More
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). 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. RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26662 P26662
• Total number of polymer chains: 4
• Total formula weight: 44902.10

Authors

Lemke, C.T. (deposition date: 2012-11-23, release date: 2013-01-02, Last modification date: 2013-03-13)

Primary citation

O'Meara, J.A.,Lemke, C.T.,Godbout, C.,Kukolj, G.,Lagace, L.,Moreau, B.,Thibeault, D.,White, P.W.,Llinas-Brunet, M.
Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance.
J.Biol.Chem., 288:5673-5681, 2013

PubMed Abstract: Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms.

PubMed: 23271737
DOI: 10.1074/jbc.M112.439455

Experimental method

X-RAY DIFFRACTION (1.9301 Å)