Protein inspired chemically orthogonal imines for linchpin directed precise and modular labeling of lysine in proteins.

We report a chemoselective, site-selective, and modular technology for precision engineering of high-frequency lysine residues in native proteins. It enables a unique, unexplored reactivity landscape on the protein surface to facilitate their single-site modification. Further, the method presents bond-architecture flexibility and enables orthogonal tagging with probes of interest.