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Phosphine‐Activated Lysine Analogues for Fast Chemical Control of Protein Subcellular Localization and Protein SUMOylation
Author(s) -
Wesalo Joshua S.,
Luo Ji,
Morihiro Kunihiko,
Liu Jihe,
Deiters Alexander
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900464
Subject(s) - sumo protein , lysine , bioorthogonal chemistry , chemistry , kinetics , biochemistry , subcellular localization , target protein , combinatorial chemistry , biophysics , biology , click chemistry , ubiquitin , amino acid , cytoplasm , gene , physics , quantum mechanics
The Staudinger reduction and its variants have exceptional compatibility with live cells but can be limited by slow kinetics. Herein we report new small‐molecule triggers that turn on proteins through a Staudinger reduction/self‐immolation cascade with substantially improved kinetics and yields. We achieved this through site‐specific incorporation of a new set of azidobenzyloxycarbonyl lysine derivatives in mammalian cells. This approach allowed us to activate proteins by adding a nontoxic, bioorthogonal phosphine trigger. We applied this methodology to control a post‐translational modification (SUMOylation) in live cells, using native modification machinery. This work significantly improves the rate, yield, and tunability of the Staudinger reduction‐based activation, paving the way for its application in other proteins and organisms.