Direct Activation of Epac by Sulfonylurea Is Isoform Selective
Direct Activation of Epac by Sulfonylurea Is Isoform Selective
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DOI：
10.1016/j.chembiol.2010.12.007
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发表时间：
2011-02-25
影响因子：
--
通讯作者：
Zhang, Jin
中科院分区：
文献类型：
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作者：
Herbst, Katie J.;Coltharp, Carla;Zhang, Jin
通常用于治疗II型糖尿病的磺脲类药物(SU)通过与磺脲受体结合来刺激胰腺13细胞分泌胰岛素。最近研究表明，SU还能激活cAMP-2直接激活的交换蛋白(Epac2)，但对这种分子作用知之甚少。通过生物传感器成像和生化分析，我们发现SU通过与Epac2直接结合来激活Epac2及其下游信号通路。我们进一步确定Epac2的R447与SU结合密切相关。这个与cAMP不同的结合部位指向Epac2变构激活的一种新模式。我们还表明，SU选择性地激活Epac2亚型，但不激活与之密切相关的Epac1，从而进一步确立了SU作为一类新的异构体选择性酶激活剂的地位。
Commonly used as a treatment for Type II diabetes, sulfonylureas (SUs) stimulate insulin secretion from pancreatic 13 cells by binding to sulfonylurea receptors. Recently, SUs have been shown to also activate exchange protein directly activated by cAMP 2 (Epac2), however, little is known about this molecular action. Using biosensor imaging and biochemical analysis, we show that SUs activate Epac2 and the downstream signaling via direct binding to Epac2. We further identify R447 of Epac2 to be critically involved in SU binding. This distinct binding site from cAMP points to a new mode of allosteric activation of Epac2. We also show that SUs selectively activate Epac2 isoform, but not the closely related Epac1, further establishing SUs as a new class of isoform-selective enzyme activators.