A selenoxide for single-atom protein modification of tyrosine residues enabled by water-resistant chalcogen and hydrogen bonding

Abstract

Abstract Post-translational modifications such as phosphorylation and acetylation are often minor structural modifications that can have profound effects on protein structure and thus broaden protein functions. Nevertheless, studying these effects directly is often out of reach because no general chemistry exists to introduce small modifications selectively; either a large, stable linker structure is selectively installed on protein residues, or a small substituent is introduced at the risk of low selectivity due to the use of reactive, indiscriminate molecules. Here we report a C–H functionalization reaction of tyrosine residues to access peptides and proteins modified by small structural changes including single-atom substitutions. A rationally designed selenoxide introduces a versatile selenonium linchpin featuring a C tyr –Se bond that can be used for further transformations at specific tyrosine residues. Key to the advance is the interplay of water-resistant, intramolecular chalcogen and hydrogen bonding of the selenoxide reagent, which allows chemo- and site-selective electrophilic aromatic substitution of tyrosine residues in aqueous solutions.