Yang, A. et al. Science 354, 623–626 (2016).

Post-translational modifications (PTMs) such as methylation and acetylation endow proteins with diverse functions. In order for such functions to be studied in detail, methods for installing specific PTMs at specific residues are needed. Yang et al. now describe a general approach for this. They used their previously reported O-phosphoserine (Sep) orthogonal translation system to introduce Sep at a desired location in a target protein. Sep can be converted via phosphate removal into a reactive dehydroalanine (Dha), which acts as a radicalophile. PTM-containing alkyl-iodide moieties can then be coupled to Dha via a metal-mediated reaction, resulting in carbon–carbon bond formation. This tool provides a straightforward approach to installing authentic PTMs onto target proteins, which the authors demonstrated for histone H3K79 as well as for ubiquitin, showing that the chemically modified proteins displayed expected biological functions.