8CX9

Structure of the SARS-COV2 PLpro (C111S) in complex with a dimeric Ubv that inhibits activity by an unusual allosteric mechanism

8CX9 の概要

• エントリーDOI: 10.2210/pdb8cx9/pdb
• 分子名称: Papain-like protease nsp3, Ubiquitin variant UbV.CV2.1, ZINC ION, ... (6 entities in total)
• 機能のキーワード: inhibitor complex, allosteric inhibition, viral protein, viral protein-signaling protein complex, viral protein/signaling protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2); 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 238772.80

構造登録者

Singer, A.U.,Slater, C.L.,Patel, A.,Russel, R.,Mark, B.L.,Sidhu, S.S. (登録日: 2022-05-20, 公開日: 2023-01-25, 最終更新日: 2024-11-06)

主引用文献

van Vliet, V.J.E.,Huynh, N.,Pala, J.,Patel, A.,Singer, A.,Slater, C.,Chung, J.,van Huizen, M.,Teyra, J.,Miersch, S.,Luu, G.K.,Ye, W.,Sharma, N.,Ganaie, S.S.,Russell, R.,Chen, C.,Maynard, M.,Amarasinghe, G.K.,Mark, B.L.,Kikkert, M.,Sidhu, S.S.
Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site.
Plos Pathog., 18:e1011065-e1011065, 2022

PubMed Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses-including SARS-CoV, MERS-CoV, and SARS-CoV-2-is the papain-like protease (PLpro). PLpro cleaves part of the viral replicase polyproteins into non-structural protein subunits, which are essential to the viral replication cycle. Additionally, PLpro can cleave both ubiquitin and the ubiquitin-like protein ISG15 from host cell substrates as a mechanism to evade innate immune responses during infection. These roles make PLpro an attractive antiviral drug target. Here we demonstrate that ubiquitin variants (UbVs) can be selected from a phage-displayed library and used to specifically and potently block SARS-CoV-2 PLpro activity. A crystal structure of SARS-CoV-2 PLpro in complex with a representative UbV reveals a dimeric UbV bound to PLpro at a site distal to the catalytic site. Yet, the UbV inhibits the essential cleavage activities of the protease in vitro and in cells, and it reduces viral replication in cell culture by almost five orders of magnitude.

PubMed: 36548304
DOI: 10.1371/journal.ppat.1011065

実験手法

X-RAY DIFFRACTION (3.5 Å)