3M5L

Crystal structure of HCV NS3/4A protease in complex with ITMN-191

3M5L の概要

• エントリーDOI: 10.2210/pdb3m5l/pdb
• 関連するPDBエントリー: 3M5M 3M5N 3M5O
• 分子名称: 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)
• 機能のキーワード: hcv, hepatitis c virus, ns3, protease, drug resistance, serine protease, chimera protein, fusion protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Hepatitis C virus subtype 1a (HCV); 詳細
• 細胞内の位置: Virion : A8DG50
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22378.62

構造登録者

Schiffer, C.A.,Romano, K.P. (登録日: 2010-03-12, 公開日: 2010-11-24, 最終更新日: 2024-02-21)

主引用文献

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

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: 21084633
DOI: 10.1073/pnas.1006370107

実験手法

X-RAY DIFFRACTION (1.25 Å)