3M5L
Crystal structure of HCV NS3/4A protease in complex with ITMN-191
Summary for 3M5L
| Entry DOI | 10.2210/pdb3m5l/pdb |
| Related | 3M5M 3M5N 3M5O |
| Descriptor | NS3/4A, (2R,6S,12Z,13aS,14aR,16aS)-6-[(tert-butoxycarbonyl)amino]-14a-[(cyclopropylsulfonyl)carbamoyl]-5,16-dioxo-1,2,3,5,6,7,8 ,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl 4-fluoro-2H-isoindole-2-carboxylate, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | hcv, hepatitis c virus, ns3, protease, drug resistance, serine protease, chimera protein, fusion protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Hepatitis C virus subtype 1a (HCV) More |
| Cellular location | Virion : A8DG50 |
| Total number of polymer chains | 1 |
| Total formula weight | 22378.62 |
| Authors | Schiffer, C.A.,Romano, K.P. (deposition date: 2010-03-12, release date: 2010-11-24, Last modification date: 2024-02-21) |
| Primary citation | Romano, K.P.,Ali, A.,Royer, W.E.,Schiffer, C.A. Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding. Proc.Natl.Acad.Sci.USA, 107:20986-20991, 2010 Cited by PubMed Abstract: Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. These findings suggest a general model for predicting the susceptibility of protease inhibitors to resistance: drugs designed to fit within the substrate envelope will be less susceptible to resistance, as mutations affecting inhibitor binding would simultaneously interfere with the recognition of viral substrates. PubMed: 21084633DOI: 10.1073/pnas.1006370107 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.25 Å) |
Structure validation
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