7WYO

Structure of the EV71 3Cpro with 338 inhibitor

7WYO の概要

• エントリーDOI: 10.2210/pdb7wyo/pdb
• 分子名称: 3C protein, N-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-ylmethyl)prop-2-enamide (3 entities in total)
• 機能のキーワード: ev71 3cpro, inhibitor, viral protein, hydrolase-hydrolase inhibitor complex
• 由来する生物種: Enterovirus A71
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 41279.35

構造登録者

Qin, B.,Hou, P.,Gao, X.,Cui, S. (登録日: 2022-02-16, 公開日: 2022-06-22, 最終更新日: 2023-11-29)

主引用文献

Qin, B.,Craven, G.B.,Hou, P.,Chesti, J.,Lu, X.,Child, E.S.,Morgan, R.M.L.,Niu, W.,Zhao, L.,Armstrong, A.,Mann, D.J.,Cui, S.
Acrylamide fragment inhibitors that induce unprecedented conformational distortions in enterovirus 71 3C and SARS-CoV-2 main protease.
Acta Pharm Sin B, 12:3924-3933, 2022

PubMed Abstract: RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins. Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine, offering the opportunity to inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that target the active site cysteine of the 3C protease (3C) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we re-purpose these hits towards the main protease (M) of SARS-CoV-2 which shares the 3C-like fold and a similar active site. The hit fragments covalently link to the catalytic cysteine of M to inhibit its activity. We demonstrate that targeting the active site cysteine of M can have profound allosteric effects, distorting secondary structures to disrupt the active dimeric unit.

PubMed: 35702321
DOI: 10.1016/j.apsb.2022.06.002

実験手法

X-RAY DIFFRACTION (1.402 Å)