Research Article

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

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Science  22 Sep 2016:
aag1465
DOI: 10.1126/science.aag1465

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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 accessing diverse proteins.

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