Global targeting of functional tyrosines using sulfur-triazole exchange chemistry.

Autor: Hahm HS; Department of Chemistry, University of Virginia, Charlottesville, VA, USA., Toroitich EK; Department of Chemistry, University of Virginia, Charlottesville, VA, USA., Borne AL; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA., Brulet JW; Department of Chemistry, University of Virginia, Charlottesville, VA, USA., Libby AH; Department of Chemistry, University of Virginia, Charlottesville, VA, USA.; University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA., Yuan K; Department of Chemistry, University of Virginia, Charlottesville, VA, USA., Ware TB; Department of Chemistry, University of Virginia, Charlottesville, VA, USA., McCloud RL; Department of Chemistry, University of Virginia, Charlottesville, VA, USA., Ciancone AM; Department of Chemistry, University of Virginia, Charlottesville, VA, USA., Hsu KL; Department of Chemistry, University of Virginia, Charlottesville, VA, USA. kenhsu@virginia.edu.; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA. kenhsu@virginia.edu.; University of Virginia Cancer Center, University of Virginia, Charlottesville, VA, USA. kenhsu@virginia.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2020 Feb; Vol. 16 (2), pp. 150-159. Date of Electronic Publication: 2019 Nov 25.
DOI: 10.1038/s41589-019-0404-5
Abstrakt: 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.
Databáze: MEDLINE
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