3P8N

Crystal structure of HCV NS3/NS4A protease complexed with BI 201335

Summary for 3P8N

• Entry DOI: 10.2210/pdb3p8n/pdb
• Related: 3P8O
• Related PRD ID: PRD_000845
• Descriptor: HCV serine protease NS3, HCV non-structural protein 4A, SODIUM ION, ... (5 entities in total)
• Functional Keywords: hepatitis c virus, ns3, ns4a, halogen bond, serine protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Hepatitis C virus (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . 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 : P26662
• Total number of polymer chains: 4
• Total formula weight: 44743.45

Authors

Lemke, C.T. (deposition date: 2010-10-14, release date: 2011-01-26, Last modification date: 2024-11-06)

Primary citation

Lemke, C.T.,Goudreau, N.,Zhao, S.,Hucke, O.,Thibeault, D.,Llinas-Brunet, M.,White, P.W.
Combined X-ray, NMR, and kinetic analyses reveal uncommon binding characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI 201335.
J.Biol.Chem., 286:11434-11443, 2011

PubMed Abstract: Hepatitis C virus infection, a major cause of liver disease worldwide, is curable, but currently approved therapies have suboptimal efficacy. Supplementing these therapies with direct-acting antiviral agents has the potential to considerably improve treatment prospects for hepatitis C virus-infected patients. The critical role played by the viral NS3 protease makes it an attractive target, and despite its shallow, solvent-exposed active site, several potent NS3 protease inhibitors are currently in the clinic. BI 201335, which is progressing through Phase IIb trials, contains a unique C-terminal carboxylic acid that binds noncovalently to the active site and a bromo-quinoline substitution on its proline residue that provides significant potency. In this work we have used stopped flow kinetics, x-ray crystallography, and NMR to characterize these distinctive features. Key findings include: slow association and dissociation rates within a single-step binding mechanism; the critical involvement of water molecules in acid binding; and protein side chain rearrangements, a bromine-oxygen halogen bond, and profound pK(a) changes within the catalytic triad associated with binding of the bromo-quinoline moiety.

PubMed: 21270126
DOI: 10.1074/jbc.M110.211417

Experimental method

X-RAY DIFFRACTION (1.9 Å)