title: 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.
abstract: 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 beta-sheet with strand E2 of the protein, with the P1 carboxylate group in the oxyanion hole.
authors.affiliation: Istituto di Ricerche di Biologia Molecolare P. Angeletti (IRBM), via Pontina Km 30.600, Pomezia (Rome), 00040, Italy.
authors.forename: D O
authors.initials: DO
authors.lastname: Cicero
authors.forename: G
authors.initials: G
authors.lastname: Barbato
authors.forename: U
authors.initials: U
authors.lastname: Koch
authors.forename: P
authors.initials: P
authors.lastname: Ingallinella
authors.forename: E
authors.initials: E
authors.lastname: Bianchi
authors.forename: M C
authors.initials: MC
authors.lastname: Nardi
authors.forename: C
authors.initials: C
authors.lastname: Steinkühler
authors.forename: R
authors.initials: R
authors.lastname: Cortese
authors.forename: V
authors.initials: V
authors.lastname: Matassa
authors.forename: R
authors.initials: R
authors.lastname: De Francesco
authors.forename: A
authors.initials: A
authors.lastname: Pessi
authors.forename: R
authors.initials: R
authors.lastname: Bazzo
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012996:Solutions; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D008024:Ligands; D009842:Oligopeptides; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D012996:Solutions; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases