Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E2 receptor EP2 subtype
Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E2 receptor EP2 subtype
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前列腺素E2受体EP2亚型的配体识别、非常规激活和G蛋白偶联
DOI：
10.1126/sciadv.abf1268
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发表时间：
2021-03-01
期刊：
影响因子：
13.6
通讯作者：
Zhang, Yan
中科院分区：
文献类型：
--
作者：
Qu, Changxiu;Mao, Chunyou;Zhang, Yan
选择性调节异源三聚体G蛋白α S亚基偶联的前列腺素E-2（PGE（2））受体EP 2亚型是骨质疏松症、高眼压症、神经退行性疾病和心血管疾病的有希望的治疗策略。在此，我们报告了EP 2-G（s）复合物及其内源性激动剂PGE（2）和两种合成激动剂taprenepag和evatanepag（CP-533536）的冷冻电子显微镜结构。这些结构揭示了EP受体家族中EP 2在其非常规受体活化和G蛋白偶联机制方面的独特特征，包括在不存在典型W-6.48“拨动开关”的情况下的活化和经由螺旋8与G（s）偶联。此外，激动剂结合的EP 2结构的检查发现了控制配体选择性的关键基序。我们的研究为EP 2激动剂识别和激活机制提供了重要的知识，并将促进针对PGE（2）信号系统的药物的合理设计。
Selective modulation of the heterotrimeric G protein alpha S subunit-coupled prostaglandin E-2 (PGE(2)) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo-electron microscopy structure of the EP2-G(s) complex with its endogenous agonist PGE(2) and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W-6.48 "toggle switch" and coupling to G(s) via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE(2) signaling system.