title: Posttranslational mutagenesis: A chemical strategy for exploring protein side-chain diversity.
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.
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Wright
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Bower
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Chalker
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Gonçalo J L
authors.initials: GJ
authors.lastname: Bernardes
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Rafal
authors.initials: R
authors.lastname: Wiewiora
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Wai-Lung
authors.initials: WL
authors.lastname: Ng
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Ritu
authors.initials: R
authors.lastname: Raj
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Faulkner
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: M Robert J
authors.initials: MR
authors.lastname: Vallée
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Anuchit
authors.initials: A
authors.lastname: Phanumartwiwath
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Coleman
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
authors.forename: Marie-Laëtitia
authors.initials: ML
authors.lastname: Thézénas
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Maola
authors.initials: M
authors.lastname: Khan
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Sébastien R G
authors.initials: SR
authors.lastname: Galan
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Lukas
authors.initials: L
authors.lastname: Lercher
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Schombs
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gerstberger
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Palm-Espling
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Baldwin
authors.affiliation: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Timothy D W
authors.initials: TD
authors.lastname: Claridge
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
authors.forename: Shabaz
authors.initials: S
authors.lastname: Mohammed
authors.affiliation: Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK. ben.davis@chem.ox.ac.uk.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Davis
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics; D031724:Bromus / Q000737:chemistry; D002244:Carbon / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry*; D005815:Genetic Code; D006031:Glycosylation; D007455:Iodine / Q000737:chemistry; D016296:Mutagenesis; D010455:Peptides / Q000737:chemistry / Q000235:genetics; D015202:Protein Engineering / Q000379:methods*; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D005609:Free Radicals; D010455:Peptides; D011506:Proteins; D002244:Carbon; D007455:Iodine; C015102:dehydroalanine; D000409:Alanine