4wh8

Crystal Structure of HCV NS3/4A protease in complex with an Asunaprevir P1-P3 macrocyclic analog.

spinqualitylabelsall models 4wh8, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4wh8 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3M7, SO4, ZN Related: 4wh6, 4wf8 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. Structural Analysis of Asunaprevir Resistance in HCV NS3/4A Protease.,Soumana DI, Ali A, Schiffer CA ACS Chem Biol. 2014 Sep 30. PMID:25243902 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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