Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes.
Nat Chem
; 15(11): 1616-1625, 2023 Nov.
Article
em En
| MEDLINE
| ID: mdl-37460812
ABSTRACT
Advances in chemoproteomic technology have revealed covalent interactions between small molecules and protein nucleophiles, primarily cysteine, on a proteome-wide scale. Most chemoproteomic screening approaches are indirect, relying on competition between electrophilic fragments and a minimalist electrophilic probe with inherently limited proteome coverage. Here we develop a chemoproteomic platform for direct electrophile-site identification based on enantiomeric pairs of clickable arylsulfonyl fluoride probes. Using stereoselective site modification as a proxy for ligandability in intact cells, we identify 634 tyrosines and lysines within functionally diverse protein sites, liganded by structurally diverse probes. Among multiple validated sites, we discover a chiral probe that modifies Y228 in the MYC binding site of the epigenetic regulator WDR5, as revealed by a high-resolution crystal structure. A distinct chiral probe stimulates tumour cell phagocytosis by covalently modifying Y387 in the recently discovered immuno-oncology target APMAP. Our work provides a deep resource of ligandable tyrosines and lysines for the development of covalent chemical probes.
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Base de dados:
MEDLINE
Assunto principal:
Proteoma
/
Lisina
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article