8EUA

Structure of SARS-CoV2 PLpro bound to a covalent inhibitor

8EUA の概要

• エントリーDOI: 10.2210/pdb8eua/pdb
• 分子名称: Papain-like protease nsp3, methyl 4-{2-[3-(2-{[(1R)-1-(naphthalen-1-yl)ethyl]carbamoyl}phenyl)propanoyl]hydrazinyl}-4-oxobutanoate, ZINC ION, ... (5 entities in total)
• 機能のキーワード: plpro, sars-cov2, covalent inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2, COVID-19 virus)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36937.99

構造登録者

Mathews, I.I.,Pokhrel, S.,Wakatsuki, S. (登録日: 2022-10-18, 公開日: 2023-04-05, 最終更新日: 2024-11-06)

主引用文献

Sanders, B.C.,Pokhrel, S.,Labbe, A.D.,Mathews, I.I.,Cooper, C.J.,Davidson, R.B.,Phillips, G.,Weiss, K.L.,Zhang, Q.,O'Neill, H.,Kaur, M.,Schmidt, J.G.,Reichard, W.,Surendranathan, S.,Parvathareddy, J.,Phillips, L.,Rainville, C.,Sterner, D.E.,Kumaran, D.,Andi, B.,Babnigg, G.,Moriarty, N.W.,Adams, P.D.,Joachimiak, A.,Hurst, B.L.,Kumar, S.,Butt, T.R.,Jonsson, C.B.,Ferrins, L.,Wakatsuki, S.,Galanie, S.,Head, M.S.,Parks, J.M.
Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2.
Nat Commun, 14:1733-1733, 2023

PubMed Abstract: Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we design a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibits PLpro with k/K = 9,600 M s, achieves sub-μM EC values against three SARS-CoV-2 variants in mammalian cell lines, and does not inhibit a panel of human deubiquitinases (DUBs) at >30 μM concentrations of inhibitor. An X-ray co-crystal structure of the compound bound to PLpro validates our design strategy and establishes the molecular basis for covalent inhibition and selectivity against structurally similar human DUBs. These findings present an opportunity for further development of covalent PLpro inhibitors.

PubMed: 36977673
DOI: 10.1038/s41467-023-37254-w

実験手法

X-RAY DIFFRACTION (3.1 Å)