6XA9

SARS CoV-2 PLpro in complex with ISG15 C-terminal domain propargylamide

6XA9 の概要

• エントリーDOI: 10.2210/pdb6xa9/pdb
• 分子名称: Non-structural protein 3, ISG15 CTD-propargylamide, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: sars cov-2, papain-like protease, isg15ctd activity based probe, covid19, hydrolase-substrate complex, hydrolase/substrate
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 135954.60

構造登録者

Klemm, T.,Calleja, D.J.,Richardson, L.W.,Lechtenberg, B.C.,Komander, D. (登録日: 2020-06-04, 公開日: 2020-06-17, 最終更新日: 2024-10-16)

主引用文献

Klemm, T.,Ebert, G.,Calleja, D.J.,Allison, C.C.,Richardson, L.W.,Bernardini, J.P.,Lu, B.G.,Kuchel, N.W.,Grohmann, C.,Shibata, Y.,Gan, Z.Y.,Cooney, J.P.,Doerflinger, M.,Au, A.E.,Blackmore, T.R.,van der Heden van Noort, G.J.,Geurink, P.P.,Ovaa, H.,Newman, J.,Riboldi-Tunnicliffe, A.,Czabotar, P.E.,Mitchell, J.P.,Feltham, R.,Lechtenberg, B.C.,Lowes, K.N.,Dewson, G.,Pellegrini, M.,Lessene, G.,Komander, D.
Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2.
Embo J., 39:e106275-e106275, 2020

PubMed Abstract: The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin-binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3,727 unique approved drugs and clinical compounds against SARS2 PLpro identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent self-processing of nsp3 in cells and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.

PubMed: 32845033
DOI: 10.15252/embj.2020106275

実験手法

X-RAY DIFFRACTION (2.9 Å)