4WH8

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

4WH8 の概要

• エントリーDOI: 10.2210/pdb4wh8/pdb
• 関連するPDBエントリー: 4WF8 4WH6
• 分子名称: Genome polyprotein, tert-butyl {(2R,4S,6S,12Z,13aS,14aR,16aS)-2-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-14a-[(cyclopropanesulfonyl)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-6-yl}carbamate, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: hcv drug resistance, protease-inhibitor complex, asunaprevir, macrocycle, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Hepatitis C virus subtype 1a
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43879.29

構造登録者

Soumana, D.I.,Ali, A.,Schiffer, C.A. (登録日: 2014-09-20, 公開日: 2014-10-15, 最終更新日: 2024-05-22)

主引用文献

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

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: 25243902
DOI: 10.1021/cb5006118

実験手法

X-RAY DIFFRACTION (2.703 Å)