Non-nucleoside analogue inhibitors bind to an allosteric site on HCV NS5B polymerase. Crystal structures and mechanism of inhibition
| Autor: | Meitian, Wang, Kenneth K-S, Ng, Maia M, Cherney, Laval, Chan, Constantin G, Yannopoulos, Jean, Bedard, Nicolas, Morin, Nghe, Nguyen-Ba, Moulay H, Alaoui-Ismaili, Richard C, Bethell, Michael N G, James |
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| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Binding Sites Dose-Response Relationship Drug Nitrogen Protein Conformation Molecular Sequence Data Hydrogen Bonding Nucleosides Viral Nonstructural Proteins Crystallography X-Ray Binding Competitive Recombinant Proteins Protein Structure Tertiary Oxygen Inhibitory Concentration 50 Models Chemical Serine Tyrosine Amino Acid Sequence Allosteric Site Protein Binding |
| Zdroj: | The Journal of biological chemistry. 278(11) |
| ISSN: | 0021-9258 |
| Popis: | X-ray crystal structures of two non-nucleoside analogue inhibitors bound to hepatitis C virus NS5B RNA-dependent RNA polymerase have been determined to 2.0 and 2.9 A resolution. These noncompetitive inhibitors bind to the same site on the protein, approximately 35 A from the active site. The common features of binding include a large hydrophobic region and two hydrogen bonds between both oxygen atoms of a carboxylate group on the inhibitor and two main chain amide nitrogen atoms of Ser(476) and Tyr(477) on NS5B. The inhibitor-binding site lies at the base of the thumb domain, near its interface with the C-terminal extension of NS5B. The location of this inhibitor-binding site suggests that the binding of these inhibitors interferes with a conformational change essential for the activity of the polymerase. |
| Databáze: | OpenAIRE |
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