4WH6
Crystal structure of HCV NS3/4A protease variant R155K in complex with Asunaprevir
Summary for 4WH6
| Entry DOI | 10.2210/pdb4wh6/pdb |
| Related | 4WF8 |
| Descriptor | Genome polyprotein, SULFATE ION, ZINC ION, ... (5 entities in total) |
| Functional Keywords | hcv drug resistant, protease-inhibitor complex, asunaprevir, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Hepatitis C virus subtype 1a |
| Total number of polymer chains | 1 |
| Total formula weight | 22239.89 |
| Authors | Soumana, D.I.,Ali, A.,Schiffer, C.A. (deposition date: 2014-09-20, release date: 2014-10-08, Last modification date: 2023-12-27) |
| Primary citation | Soumana, D.I.,Ali, A.,Schiffer, C.A. Structural Analysis of Asunaprevir Resistance in HCV NS3/4A Protease. Acs Chem.Biol., 9:2485-2490, 2014 Cited by PubMed Abstract: Asunaprevir (ASV), an isoquinoline-based competitive inhibitor targeting the hepatitis C virus (HCV) NS3/4A protease, is very potent in vivo. However, the potency is significantly compromised by the drug resistance mutations R155K and D168A. In this study three crystal structures of ASV and an analogue were determined to analyze the structural basis of drug resistance susceptibility. These structures revealed that ASV makes extensive contacts with Arg155 outside the substrate envelope. Arg155 in turn is stabilized by Asp168, and thus when either residue is mutated, the enzyme's interaction with ASV's P2* isoquinoline is disrupted. Adding a P1-P3 macrocycle to ASV enhances the inhibitor's resistance barrier, likely due to poising the inhibitor to its bound conformation. Macrocyclic inhibitors with P2* extension moieties avoiding interaction with the protease S2 residues including Arg155 must be chosen for future design of more robust protease inhibitors. PubMed: 25243902DOI: 10.1021/cb5006118 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.99 Å) |
Structure validation
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