Posttranslational mutagenesis: A chemical strategy for exploring protein side-chain diversity

Tom Wright, Ben Bower, Justin Chalker, Gonçalo Bernardes, Rafal Wiewiora, Wai-Lung Ng, Ritu Raj, Sarah Faulkner, M. Vallée, Anuchit Phanumartwiwath, Oliver Coleman, Marie-Laëtitia Thézénas, Maola Khan, Sébastien Galan, Lukas Lercher, Matthew Schombs, Stefanie Gerstberger, Maria Palm-Espling, Andrew Baldwin, Benedikt KesslerTimothy Claridge, Shabaz Mohammed, Benjamin Davis

    Research output: Contribution to journalArticlepeer-review

    197 Citations (Scopus)


    Posttranslational modification of proteins expands their structural and functional capabilities beyond those directly specified by the genetic code. However, the vast diversity of chemically plausible (including unnatural but functionally relevant) side chains is not readily accessible. We describe C (sp3)-C (sp3) bond-forming reactions on proteins under biocompatible conditions, which exploit unusual carbon free-radical chemistry, and use them to form Cb-Cg bonds with altered side chains.We demonstrate how these transformations enable a wide diversity of natural, unnatural, posttranslationally modified (methylated, glycosylated, phosphorylated, hydroxylated), and labeled (fluorinated, isotopically labeled) side chains to be added to a common, readily accessible dehydroalanine precursor in a range of representative protein types and scaffolds. This approach, outside of the rigid constraints of the ribosome and enzymatic processing, may be modified more generally for access to diverse proteins.

    Original languageEnglish
    Article numberaag1465
    Number of pages18
    Issue number6312
    Early online date2016
    Publication statusPublished - 4 Nov 2016


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