Covalent protein modification: the current landscape of residue-specific electrophiles

•Electrophiles can show distinct amino-acid selectivities in proteomes.•The judicious selection of an electrophile is critical to various chemical-proteomic applications.•A wide array of serine and cysteine-directed electrophiles with varying reactivity is available.•Ample opportunities for electrophile development exist for other reactive residues such as lysine, threonine, aspartate and glutamate. Functional amino acids that play critical roles in catalysis and regulation are known to display elevated nucleophilicity and can be selectively targeted for covalent modification by reactive electrophiles. Chemical-proteomic platforms, such as activity-based protein profiling (ABPP), exploit this reactivity by utilizing chemical probes to covalently modify active-site residues to inform on the functional state of enzymes within complex proteomes. These and other applications rely on the availability of a diverse array of electrophiles and detailed knowledge of the reactivity and amino-acid selectivity of these groups. Here, we survey the current landscape of electrophiles that covalently target various nucleophilic amino acids in proteins and highlight proteomic applications that have benefited from the unique properties of these electrophiles.