Meng Xue, Li Yang, Xu Jiuyin, Wu Kai, Hu Wen, Wu Canrong, Xu H Eric, Xu Youwei
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2423840122. doi: 10.1073/pnas.2423840122. Epub 2025 May 14.
Prostaglandin E (PGE) mediates diverse physiological processes through four G protein-coupled receptor subtypes (EP1-EP4). While structures of EP2, EP3, and EP4 have been determined, the structural basis for PGE recognition and activation of the EP1 receptor subtype has remained elusive due to its inherent instability. Here, we present the cryoelectron microscopy structure of the human EP1 receptor in complex with PGE and heterotrimeric Gq protein at 2.55 Å resolution, completing the structural characterization of the EP receptor family. Our structure reveals a unique binding mode of PGE within EP1, involving key interactions with residues in the orthosteric pocket. Notably, we observe a less pronounced outward displacement of transmembrane helix 6 compared to other EP receptor subtypes, suggesting a distinct activation mechanism for EP1. Through extensive mutational analyses, we identify critical residues involved in PGE recognition, EP1 activation, and Gq protein coupling. By overcoming the challenges associated with the instability of EP1, our findings provide valuable insights into the subtype-specific activation mechanisms of EP receptors and lay the foundation for the development of more selective EP1-targeted therapeutics.
前列腺素E（PGE）通过四种G蛋白偶联受体亚型（EP1-EP4）介导多种生理过程。虽然EP2、EP3和EP4的结构已被确定，但由于EP1受体亚型固有的不稳定性，其识别和激活PGE的结构基础仍然难以捉摸。在这里，我们展示了与PGE和异源三聚体Gq蛋白结合的人EP1受体的冷冻电镜结构，分辨率为2.55 Å，完成了EP受体家族的结构表征。我们的结构揭示了PGE在EP1内独特的结合模式，涉及与正构口袋中残基的关键相互作用。值得注意的是，与其他EP受体亚型相比，我们观察到跨膜螺旋6向外位移不明显，这表明EP1有独特的激活机制。通过广泛的突变分析，我们确定了参与PGE识别、EP1激活和Gq蛋白偶联的关键残基。通过克服与EP1不稳定性相关的挑战，我们的研究结果为EP受体的亚型特异性激活机制提供了有价值的见解，并为开发更具选择性的EP1靶向治疗药物奠定了基础。
