2. Academic Validation
  3. Posttranslational mutagenesis: A chemical strategy for exploring protein side-chain diversity

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

  • Science. 2016 Nov 4;354(6312):aag1465. doi: 10.1126/science.aag1465.
Tom H Wright 1,  Ben J Bower 1,  Justin M Chalker 1,  Gonçalo J L Bernardes 1,  Rafal Wiewiora 1,  Wai-Lung Ng 1,  Ritu Raj 1,  Sarah Faulkner 1,  M Robert J Vallée 1,  Anuchit Phanumartwiwath 1,  Oliver D Coleman 1,  Marie-Laëtitia Thézénas 2,  Maola Khan 1,  Sébastien R G Galan 1,  Lukas Lercher 1,  Matthew W Schombs 1,  Stefanie Gerstberger 1,  Maria E Palm-Espling 1,  Andrew J Baldwin 1,  Benedikt M Kessler 2,  Timothy D W Claridge 1,  Shabaz Mohammed 1,  Benjamin G Davis 3
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • 2 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
  • 3 Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK. ben.davis@chem.ox.ac.uk.
PMID: 27708059 DOI: 10.1126/science.aag1465
Abstract

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 Cβ-Cγ 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.

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