The discerning reactivity of sulfur(vi)-fluoride exchange (SuFEx) chemistry has enabled the context-specific labeling of protein binding sites by chemical probes that incorporate these versatile warheads. Emerging information from protein-probe structures and proteomic mapping experiments is helping advance our understanding of the protein microenvironment that dictates the reactivity of targetable amino acid residues. This review explores these new findings that should influence the future rational design of SuFEx probes for a multitude of applications in chemical biology and drug discovery.
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