Structural characterization of the interactions of optimized product inhibitors with the N-terminal proteinase domain of the hepatitis C virus (HCV) NS3 protein by NMR and modelling studies

• Published in: Journal of molecular biology 1999-06, Vol.289 (2), p.385-396
• Main Authors: Cicero, Daniel O, Barbato, Gaetano, Koch, Uwe, Ingallinella, Paolo, Bianchi, Elisabetta, Nardi, M.Chiara, Steinkühler, Christian, Cortese, Riccardo, Matassa, Victor, De Francesco, Raffaele, Pessi, Antonello, Bazzo, Renzo
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; binding; Binding Sites; HCV; Hepacivirus - enzymology; Hepatitis C virus; Humans; inhibitors; Ligands; Models, Molecular; NMR; NS3-proteinase; Nuclear Magnetic Resonance, Biomolecular; Oligopeptides - chemistry; Oligopeptides - pharmacology; Protein Conformation; Protein Structure, Secondary; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors - pharmacology; Solutions; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - chemistry; Viral Nonstructural Proteins - metabolism
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1006/jmbi.1999.2746

The interactions of peptide inhibitors, obtained by the optimization of N-terminal cleavage products of natural substrates, with the protease of human hepatitis C virus (HCV) are characterized by NMR and modelling studies. The S-binding region of the enzyme and the bound conformation of the ligands are experimentally determined. The NMR data are then used as the experimental basis for modelling studies of the structure of the complex. The S-binding region involves the loop connecting strands E2 and F2, and appears shallow and solvent-exposed. The ligand binds in an extended conformation, forming an antiparallel β-sheet with strand E2 of the protein, with the P1 carboxylate group in the oxyanion hole.