Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity

被引:155
作者
Bayle, JH
Grimley, JS
Stankunas, K
Gestwicki, JE
Wandless, TJ
Crabtree, GR [1 ]
机构
[1] Stanford Univ, Sch Med, Dept Pathol, Palo Alto, CA 94304 USA
[2] Stanford Univ, Sch Med, Dept Dev Biol, Palo Alto, CA 94304 USA
[3] Stanford Univ, Sch Med, Dept Mol Pharmacol, Palo Alto, CA 94304 USA
[4] Stanford Univ, Sch Med, Howard Hughes Med Inst, Palo Alto, CA 94304 USA
来源
CHEMISTRY & BIOLOGY | 2006年 / 13卷 / 01期
关键词
D O I
10.1016/j.chembiol.2005.10.017
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:99 / 107
页数:9
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