Nucleophilic covalent ligand discovery for the cysteine redoxome.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
16
06
2022
accepted:
07
04
2023
medline:
30
10
2023
pubmed:
30
5
2023
entrez:
29
5
2023
Statut:
ppublish
Résumé
With an eye toward expanding chemistries used for covalent ligand discovery, we elaborated an umpolung strategy that exploits the 'polarity reversal' of sulfur when cysteine is oxidized to sulfenic acid, a widespread post-translational modification, for selective bioconjugation with C-nucleophiles. Here we present a global map of a human sulfenome that is susceptible to covalent modification by members of a nucleophilic fragment library. More than 500 liganded sulfenic acids were identified on proteins across diverse functional classes, and, of these, more than 80% were not targeted by electrophilic fragment analogs. We further show that members of our nucleophilic fragment library can impair functional protein-protein interactions involved in nuclear oncoprotein transport and DNA damage repair. Our findings reveal a vast expanse of ligandable sulfenic acids in the human proteome and highlight the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline, presaging further opportunities using non-traditional chemistries for targeting proteins.
Identifiants
pubmed: 37248412
doi: 10.1038/s41589-023-01330-5
pii: 10.1038/s41589-023-01330-5
doi:
Substances chimiques
Cysteine
K848JZ4886
Ligands
0
Sulfenic Acids
0
Proteome
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1309-1319Subventions
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : GM102187
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : GM087638
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 21922702
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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