Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity
Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity
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DOI：
10.1016/j.chembiol.2005.10.017
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发表时间：
2006-01-01
影响因子：
--
通讯作者：
Crabtree, GR
中科院分区：
文献类型：
--
作者：
Bayle, JH;Grimley, JS;Crabtree, GR
利用小分子调控蛋白质二聚作用在蛋白质功能研究中有着广泛的应用。雷帕霉素有两个结合面：一个与FKBP12结合，另一个与mTOR/FRAP的FRB结构域结合，指导它们的二聚化。雷帕霉素是一种有效的细胞生长抑制剂，但表面接触FRB的化学修饰可以减轻这种影响。通过突变FRB以适应雷帕罗星类似物(A Rapalog)，可以恢复与FRB融合蛋白的有效相互作用。我们已经定量地评估了在C16和C20功能化的Rapalog与一组FRb突变体之间的相互作用。几种药物-FRB突变组合具有不同且不重叠的特异性。这些FRB-Rapalog合作伙伴允许选择性控制不同的FRB融合蛋白，而不会发生交叉反应。多靶点蛋白质的正交控制拓宽了化学诱导二聚化的能力，以调节生物过程。
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.