Global Targeting of Functional Tyrosines Using Sulfur-triazole Exchange Chemistry

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2019 Nov 27

PMID 31768034

Citations 59

Authors

Heung Sik Hahm

Emmanuel K Toroitich

Adam L Borne

Jeffrey W Brulet

Adam H Libby

Kun Yuan

Timothy B Ware

Rebecca L McCloud

Anthony M Ciancone

Ku-Lung Hsu

Affiliations

Soon will be listed here.

Abstract

Covalent probes serve as valuable tools for global investigation of protein function and ligand binding capacity. Despite efforts to expand coverage of residues available for chemical proteomics (e.g., cysteine and lysine), a large fraction of the proteome remains inaccessible with current activity-based probes. Here, we introduce sulfur-triazole exchange (SuTEx) chemistry as a tunable platform for developing covalent probes with broad applications for chemical proteomics. We show modifications to the triazole leaving group can furnish sulfonyl probes with ~5-fold enhanced chemoselectivity for tyrosines over other nucleophilic amino acids to investigate more than 10,000 tyrosine sites in lysates and live cells. We discover that tyrosines with enhanced nucleophilicity are enriched in enzymatic, protein-protein interaction and nucleotide recognition domains. We apply SuTEx as a chemical phosphoproteomics strategy to monitor activation of phosphotyrosine sites. Collectively, we describe SuTEx as a biocompatible chemistry for chemical biology investigations of the human proteome.

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