title: Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity.
abstract: Controlling protein dimerization with small molecules has broad application to the study of protein function. Rapamycin has two binding surfaces: one that binds to FKBP12 and the other to the Frb domain of mTor/FRAP, directing their dimerization. Rapamycin is a potent cell growth inhibitor, but chemical modification of the surface contacting Frb alleviates this effect. Productive interactions with Frb-fused proteins can be restored by mutation of Frb to accommodate the rapamycin analog (a rapalog). We have quantitatively assessed the interaction between rapalogs functionalized at C16 and C20 and a panel of Frb mutants. Several drug-Frb mutant combinations have different and nonoverlapping specificities. These Frb-rapalog partners permit the selective control of different Frb fusion proteins without crossreaction. The orthogonal control of multiple target proteins broadens the capabilities of chemical induction of dimerization to regulate biologic processes.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Palo Alto, California 94304, USA.
authors.forename: J Henri
authors.initials: JH
authors.lastname: Bayle
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Grimley
authors.forename: Kryn
authors.initials: K
authors.lastname: Stankunas
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wandless
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Crabtree
mesh_terms: D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D011494:Protein Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus