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Structural insights into the activation of the human prostaglandin E2 receptor EP1 subtype by prostaglandin E2

文献类型：期刊论文

作者Meng, Xue5,6; Li, Yang4,6; Xu, Jiuyin3,5,6; Wu, Kai6; Hu, Wen6; Wu, Canrong2,6; Xu, H. Eric2,3,4,5,6; Xu, Youwei1,6
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2025-05-20
卷号122期号:20页码:12
关键词prostaglandin E2 EP1 receptor activation PGE2 selectivity
ISSN号0027-8424
DOI10.1073/pnas.2423840122
英文摘要Prostaglandin E2 (PGE2) 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 PGE2 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 PGE2 and heterotrimeric Gq protein at 2.55 & Aring; resolution, completing the structural characterization of the EP receptor family. Our structure reveals a unique binding mode of PGE2 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 PGE2 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.
WOS关键词CRYO-EM STRUCTURE ; PROSTANOID RECEPTORS ; EXPRESSION ; CLONING ; HYPERTENSION ; SYSTEM
资助项目National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[32130022] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Lingang Laboratory[LG-GG-202204-01] ; National Key R&D Program of China[2022YFC2703105] ; National Natural Science Foundation of China[81902085]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001496129600001
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/317944]  
专题新药研究国家重点实验室
通讯作者Xu, H. Eric; Xu, Youwei
作者单位1.Guangzhou Med Univ, Sch Pharmaceut Sci, Guangzhou Municipal & Guangdong Prov Key Lab Mol T, Natl Med Prod Adm & State Key Lab Resp Dis, Guangzhou 511436, Guangdong, Peoples R China
2.Shanghai Jiao Tong Univ, Ruijin Hosp, Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai,Sch Med,State K, Shanghai 200025, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Meng, Xue,Li, Yang,Xu, Jiuyin,et al. Structural insights into the activation of the human prostaglandin E2 receptor EP1 subtype by prostaglandin E2[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2025,122(20):12.
APA Meng, Xue.,Li, Yang.,Xu, Jiuyin.,Wu, Kai.,Hu, Wen.,...&Xu, Youwei.(2025).Structural insights into the activation of the human prostaglandin E2 receptor EP1 subtype by prostaglandin E2.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,122(20),12.
MLA Meng, Xue,et al."Structural insights into the activation of the human prostaglandin E2 receptor EP1 subtype by prostaglandin E2".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 122.20(2025):12.

入库方式： OAI收割

来源：上海药物研究所

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