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A Bioorthogonal Small‐Molecule‐Switch System for Controlling Protein Function in Live Cells
Author(s) -
Liu Peng,
Calderon Abram,
Konstantinidis Georgios,
Hou Jian,
Voss Stephanie,
Chen Xi,
Li Fu,
Banerjee Soumya,
Hoffmann JanErik,
Theiss Christiane,
Dehmelt Leif,
Wu YaoWen
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201403463
Subject(s) - bioorthogonal chemistry , function (biology) , small molecule , microbiology and biotechnology , chemistry , biology , combinatorial chemistry , biochemistry , click chemistry
Chemically induced dimerization (CID) has proven to be a powerful tool for modulating protein interactions. However, the traditional dimerizer rapamycin has limitations in certain in vivo applications because of its slow reversibility and its affinity for endogenous proteins. Described herein is a bioorthogonal system for rapidly reversible CID. A novel dimerizer with synthetic ligand of FKBP′ (SLF′) linked to trimethoprim (TMP). The SLF′ moiety binds to the F36V mutant of FK506‐binding protein (FKBP) and the TMP moiety binds to E. coli dihydrofolate reductase (eDHFR). SLF′‐TMP‐induced heterodimerization of FKBP(F36V) and eDHFR with a dissociation constant of 0.12 μ M . Addition of TMP alone was sufficient to rapidly disrupt this heterodimerization. Two examples are presented to demonstrate that this system is an invaluable tool, which can be widely used to rapidly and reversibly control protein function in vivo.