PDBsum entry 3p8o

Hydrolase/hydrolase inhibitor

PDB id: 3p8o

Contents

Protein chains

182 a.a.

13 a.a.

Ligands

L5T ×2

Metals

_NA ×2

Waters ×66

References listed in PDB file

Key reference

• Title: Combined X-Ray, Nmr, And kinetic analyses reveal uncommon binding characteristics of the hepatitis c virus ns3-Ns4a protease inhibitor bi 201335.
• Authors: C.T.Lemke, N.Goudreau, S.Zhao, O.Hucke, D.Thibeault, M.Llinàs-Brunet, P.W.White.
• Ref.: J Biol Chem, 2011, 286, 11434-11443. [DOI no: 10.1074/jbc.M110.211417]
• PubMed id: 21270126

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.