Targeted sulfur(VI) fluoride exchange-mediated covalent modification of a tyrosine residue in the catalytic pocket of tyrosyl-DNA phosphodiesterase 1.

ABSTRACT: Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) has been challenging because of the enzyme shallow catalytic pocket and non-specific substrate binding interactions. Recently, we discovered a quinolone-binding hot spot in TDP1's 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 insights into the biological roles of proteins and inform ligand design. As we report herein, we used SuFEx chemistries to prepare covalent TDP1-bound binders showing site-specific covalent bonds with Y204. Our work presents the first applic

SUBMITTER: Zhao XZ 

PROVIDER: S-EPMC11405833 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature