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

Journal article

Post-translational 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 C–C bonds with altered side chains. We demonstrate how these transformations enable a wide-diversity of natural, unnatural, post-translationally-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 accessing diverse proteins.

Authors: Wright, T; Bower, B; Chalker, J; Bernardes, G; Wiewiora, R

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for the Advancement of Science
• Journal: Science
• Publication date: 2016-09-01
• Acceptance date: 2016-09-12
• DOI: 10.1126/science.aag1465
• EISSN: 1095-9203
• ISSN: 1095-9203, 0036-8075
• Pmid: 27708059
• Keywords: Journal Article