Hepatitis C virus NS3 protease requires its NS4A cofactor peptide for optimal binding of a boronic acid inhibitor as shown by NMR.
Chem Biol
; 9(1): 79-92, 2002 Jan.
Article
em En
| MEDLINE
| ID: mdl-11841941
ABSTRACT
NMR spectroscopy was used to characterize the hepatitis C virus (HCV) NS3 protease in a complex with the 24 residue peptide cofactor from NS4A and a boronic acid inhibitor, Ac-Asp-Glu-Val-Val-Pro-boroAlg-OH. Secondary-structure information, NOE constraints between protease and cofactor, and hydrogen-deuterium exchange rates revealed that the cofactor was an integral strand in the N-terminal beta-sheet of the complex as observed in X-ray crystal structures. Based upon chemical-shift perturbations, inhibitor-protein NOEs, and the protonation state of the catalytic histidine, the boronic acid inhibitor was bound in the substrate binding site as a transition state mimic. In the absence of cofactor, the inhibitor had a lower affinity for the protease. Although the inhibitor binds in the same location, differences were observed at the catalytic site of the protease.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
/
Proteínas Virais
/
Ácidos Borônicos
/
Proteínas de Transporte
/
Proteínas não Estruturais Virais
/
Hepacivirus
Limite:
Humans
Idioma:
En
Ano de publicação:
2002
Tipo de documento:
Article