MacDonald, J.I. et al. Nat. Chem. Biol. 11, 326–331 (2015).

There exists a continuing need for novel approaches to chemically modify proteins at specific sites for applications in various research fields. Most methods require some amount of genetic engineering. MacDonald et al. present new chemistry for modifying native protein N termini that does not require any genetic engineering and that proceeds under mild conditions. They show that N-terminal amines react specifically and efficiently with a 2-pyridinecarboxyaldehyde to form a stable imidazolidinone product and that protein function is not adversely affected. They demonstrated the reaction for 12 diverse proteins, showing that it should be useful under many circumstances, such as for tagging proteins with biotin, fluorescent dyes, targeting moieties or affinity tags, to name just a few applications.