TY - JOUR
T1 - Posttranslational mutagenesis: A chemical strategy for exploring protein side-chain diversity
AU - Wright, Tom
AU - Bower, Ben
AU - Chalker, Justin
AU - Bernardes, Gonçalo
AU - Wiewiora, Rafal
AU - Ng, Wai-Lung
AU - Raj, Ritu
AU - Faulkner, Sarah
AU - Vallée, M.
AU - Phanumartwiwath, Anuchit
AU - Coleman, Oliver
AU - Thézénas, Marie-Laëtitia
AU - Khan, Maola
AU - Galan, Sébastien
AU - Lercher, Lukas
AU - Schombs, Matthew
AU - Gerstberger, Stefanie
AU - Palm-Espling, Maria
AU - Baldwin, Andrew
AU - Kessler, Benedikt
AU - Claridge, Timothy
AU - Mohammed, Shabaz
AU - Davis, Benjamin
PY - 2016/11/4
Y1 - 2016/11/4
N2 - 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 Cb-Cg 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.
AB - 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 Cb-Cg 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.
UR - http://www.scopus.com/inward/record.url?scp=84988557073&partnerID=8YFLogxK
U2 - 10.1126/science.aag1465
DO - 10.1126/science.aag1465
M3 - Article
SN - 0036-8075
VL - 354
JO - Science
JF - Science
IS - 6312
M1 - aag1465
ER -