9EEI

Crystal structure of the SARS-CoV-2 Omicron nsp5 main protease (Mpro) E166V mutant in complex with inhibitor GC376

9EEI の概要

• エントリーDOI: 10.2210/pdb9eei/pdb
• 関連するPDBエントリー: 8TXI
• 関連するBIRD辞書のPRD_ID: PRD_002495
• 分子名称: 3C-like proteinase nsp5, N~2~-[(benzyloxy)carbonyl]-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide (2 entities in total)
• 機能のキーワード: viral protein, nsp5, sars-cov-2, gc376, drug resistance, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34242.08

構造登録者

Neilsen, G.,Kirby, K.A.,Sarafianos, S.G. (登録日: 2024-11-19, 公開日: 2025-06-18)

主引用文献

Neilsen, G.,Lan, S.,Slack, R.L.,Lorson, Z.C.,Emanuelli Castaner, A.,Lee, R.,Edwards, K.G.,Zhang, H.,Lee, J.,Cantara, W.A.,Cilento, M.E.,Zhang, H.,De, R.,Amblard, F.,Tedbury, P.R.,Kirby, K.A.,Schinazi, R.F.,Sarafianos, S.G.
Strategy to overcome a nirmatrelvir resistance mechanism in the SARS-CoV-2 nsp5 protease.
Sci Adv, 11:eadv8875-eadv8875, 2025

PubMed Abstract: E166V in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp5 protease confers strong resistance to the antiviral component of Paxlovid, nirmatrelvir (NIR), in passaging and clinical samples. In SARS-CoV-2 replicons, E166V drastically decreased Washington (WA1) but not Omicron (BA.1) fitness (20- versus 2-fold), suggesting a lower barrier to resistance in the BA.1 strain and consistent with observed differences in respective nsp5 dimerization affinities. Crystal structures reveal a steric clash between the rigid, bulky NIR -butyl group and the β-branched Val, disrupting the covalent binding of NIR to the catalytic Cys and leading to high resistance in BA.1 and WA1 replicons. NIR-resistant replicons remained susceptible to GC376, which can still covalently bind Cys by avoiding a steric clash with Val through "wiggling and jiggling." Hence, strategic flexibility is a strategy that will help design second-generation antivirals against NIR-resistant viruses.

PubMed: 40479048
DOI: 10.1126/sciadv.adv8875

実験手法

X-RAY DIFFRACTION (2.76 Å)