8VEC

Deep Mutational Scanning of SARS-CoV-2 PLpro

8VEC の概要

• エントリーDOI: 10.2210/pdb8vec/pdb
• 分子名称: Papain-like protease nsp3, ZINC ION (3 entities in total)
• 機能のキーワード: papain-like protease, sars-cov-2, mutation, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36103.28

構造登録者

Wu, X.,Nguyen, J.V.,Call, M.E.,Call, M.J. (登録日: 2023-12-18, 公開日: 2024-03-20, 最終更新日: 2024-08-07)

主引用文献

Wu, X.,Go, M.,Nguyen, J.V.,Kuchel, N.W.,Lu, B.G.C.,Zeglinski, K.,Lowes, K.N.,Calleja, D.J.,Mitchell, J.P.,Lessene, G.,Komander, D.,Call, M.E.,Call, M.J.
Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape.
Nat Commun, 15:6219-6219, 2024

PubMed Abstract: Papain-like protease (PLpro) is an attractive drug target for SARS-CoV-2 because it is essential for viral replication, cleaving viral poly-proteins pp1a and pp1ab, and has de-ubiquitylation and de-ISGylation activities, affecting innate immune responses. We employ Deep Mutational Scanning to evaluate the mutational effects on PLpro enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify mutations in neighboring residues that alter activity. We characterize residues responsible for substrate binding and demonstrate that although residues in the blocking loop are remarkably tolerant to mutation, blocking loop flexibility is important for function. We additionally find a connected network of mutations affecting activity that extends far from the active site. We leverage our library to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.

PubMed: 39043718
DOI: 10.1038/s41467-024-50566-9

実験手法

X-RAY DIFFRACTION (2 Å)