MassIVE MSV000095388

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Targeted SuFEx-mediated covalent modification of a tyrosine residue in the catalytic pocket of tyrosyl-DNA phosphodiesterase 1

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Description

Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) is complicated by the shallow catalytic pocket and the difficulties of overcoming binding interactions of substrate. Recently, we discovered a quinolone-binding hot spot in TDP1s active site proximal to the evolutionary conserved Y204 and F259 residues that position DNA. Sulfur (VI) fluoride exchange (SuFEx) is a biocompatible click chemistry reaction that enables acylation of protein residues, including tyrosine. Selective protein modifications can provide valuable insights into the biological roles of proteins and inform ligand design. As we report herein, we used SuFEx chemistries to prepare several covalent TDP1-bound binders showing site-specific covalent bonds with Y204. Our work presents the first application of SuFEx chemistries to TDP1-binding ligands. It validates the ability to covalently modify specific TDP1 residues by designed targeting. Adding this capability to the chemical biology toolbox of resources for studying TDP1 could have far reaching consequences. [doi:10.25345/C52V2CN4H] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TDP1 ; SuFEx ; Tyrosine

Contact

Principal Investigators:
(in alphabetical order) 		Terrence Burke, National Cancer Institute, United States
Submitting User: kiallsuazo
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