Hepatitis C Virus NS3 Protease Requires Its NS4A Cofactor Peptide for Optimal Binding of a Boronic Acid Inhibitor as Shown by NMR
| Autor: | Zhongren J. Wu, Daniel M. Camac, Peter J. Domaille, Zelda R. Wasserman, Sharon J. Archer, Lawrence J. Mersinger, Charles A. Kettner, Christopher J. Rizzo, Marina Bukhtiyarova, Sharada Jagannathan, Neil A. Farrow |
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| Rok vydání: | 2002 |
| Předmět: |
inorganic chemicals
Magnetic Resonance Spectroscopy medicine.medical_treatment Clinical Biochemistry Peptide Hepacivirus Viral Nonstructural Proteins Crystallography X-Ray Biochemistry Cofactor chemistry.chemical_compound Viral Proteins Drug Discovery medicine Humans Protease Inhibitors Binding site Molecular Biology Histidine chemistry.chemical_classification Pharmacology NS3 Protease Binding Sites biology Intracellular Signaling Peptides and Proteins General Medicine Nuclear magnetic resonance spectroscopy Boronic Acids chemistry biology.protein Molecular Medicine Carrier Proteins Boronic acid |
| Zdroj: | Chemistry & Biology. 9(1):79-92 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/s1074-5521(01)00096-5 |
| Popis: | 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 β-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. |
| Databáze: | OpenAIRE |
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