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Posttranslational mutagenesis: A chemical strategy for exploring protein side-chain diversity.
Wright, Tom H; Bower, Ben J; Chalker, Justin M; Bernardes, Gonçalo J L; Wiewiora, Rafal; Ng, Wai-Lung; Raj, Ritu; Faulkner, Sarah; Vallée, M Robert J; Phanumartwiwath, Anuchit; Coleman, Oliver D; Thézénas, Marie-Laëtitia; Khan, Maola; Galan, Sébastien R G; Lercher, Lukas; Schombs, Matthew W; Gerstberger, Stefanie; Palm-Espling, Maria E; Baldwin, Andrew J; Kessler, Benedikt M; Claridge, Timothy D W; Mohammed, Shabaz; Davis, Benjamin G.
Affiliation
  • Wright TH; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Bower BJ; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Chalker JM; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Bernardes GJ; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Wiewiora R; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Ng WL; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Raj R; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Faulkner S; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Vallée MR; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Phanumartwiwath A; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Coleman OD; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Thézénas ML; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
  • Khan M; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Galan SR; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Lercher L; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Schombs MW; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Gerstberger S; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Palm-Espling ME; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Baldwin AJ; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Kessler BM; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
  • Claridge TD; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Mohammed S; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
  • Davis BG; Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK. ben.davis@chem.ox.ac.uk.
Science ; 354(6312)2016 11 04.
Article in En | MEDLINE | ID: mdl-27708059
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 Cß-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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Collection: 01-internacional Database: MEDLINE Main subject: Carbon / Protein Engineering / Proteins / Protein Processing, Post-Translational / Alanine / Free Radicals Language: En Journal: Science Year: 2016 Document type: Article Affiliation country: United kingdom
Search on Google
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Collection: 01-internacional Database: MEDLINE Main subject: Carbon / Protein Engineering / Proteins / Protein Processing, Post-Translational / Alanine / Free Radicals Language: En Journal: Science Year: 2016 Document type: Article Affiliation country: United kingdom