8F93

WDR5 covalently modified at Y228 by (R)-2-SF

Summary for 8F93

• Entry DOI: 10.2210/pdb8f93/pdb
• Descriptor: WD repeat-containing protein 5, 3-ethynyl-5-{[(3R)-4-{1-[(2-methoxyphenyl)methyl]-1H-benzimidazole-5-carbonyl}-3-methylpiperazin-1-yl]methyl}benzene-1-sulfonyl fluoride, GLYCEROL, ... (6 entities in total)
• Functional Keywords: covalent inhibition, y228, sulfonyl fluoride, ppi, gene regulation, gene regulation-inhibitor complex, gene regulation/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 71079.19

Authors

Taunton, J.,Craven, G.B.,Chen, Y. (deposition date: 2022-11-23, release date: 2023-05-31, Last modification date: 2024-11-06)

Primary citation

Chen, Y.,Craven, G.B.,Kamber, R.A.,Cuesta, A.,Zhersh, S.,Moroz, Y.S.,Bassik, M.C.,Taunton, J.
Direct mapping of ligandable tyrosines and lysines in cells with chiral sulfonyl fluoride probes.
Nat.Chem., 15:1616-1625, 2023

PubMed 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.

PubMed: 37460812
DOI: 10.1038/s41557-023-01281-3

Experimental method

X-RAY DIFFRACTION (2.3 Å)