Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
23 Jul 2024
23 Jul 2024
Historique:
received:
24
02
2024
accepted:
12
07
2024
medline:
24
7
2024
pubmed:
24
7
2024
entrez:
23
7
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39043718
doi: 10.1038/s41467-024-50566-9
pii: 10.1038/s41467-024-50566-9
doi:
Substances chimiques
papain-like protease, SARS-CoV-2
EC 3.4.22.2
Coronavirus Papain-Like Proteases
EC 3.4.22.2
Antiviral Agents
0
Coronavirus 3C Proteases
EC 3.4.22.28
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6219Subventions
Organisme : Wellcome Trust (Wellcome)
ID : 222698/Z/21/Z
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : GNT2016461
Organisme : Department of Health | National Health and Medical Research Council (NHMRC)
ID : GNT1178122
Informations de copyright
© 2024. The Author(s).
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