Structural insights into selective and dual antagonism of EP2 and EP4 prostaglandin receptors
文献类型：期刊论文
| 作者 | Wu, Yanli1; Zhang, Heng1; Xu, Jiuyin4; Wu, Kai1; Hu, Wen1; He, Xinheng1; Wang, Gaoming3; Wu, Canrong4; Xu, H. Eric1,2,4 |
| 刊名 | EMBO JOURNAL
 |
| 出版日期 | 2025-10-29 |
| 页码 | 21 |
| 关键词 | Cryo-EM EP2 EP4 Selective Antagonist Dual Antagonist |
| ISSN号 | 0261-4189 |
| DOI | 10.1038/s44318-025-00611-0 |
| 英文摘要 | Prostaglandin E2 (PGE2) signaling through EP2 and EP4 receptors is crucial in regulating inflammation, pain, and cancer progression. While selective and dual antagonists for these receptors hold therapeutic potential, their binding mechanisms and selectivity have remained unclear. In this study, we present cryo-electron microscopy (cryo-EM) structures of human EP2 and EP4 receptors in complex with selective antagonists PF-04418948 and grapiprant, as well as with the dual antagonist TG6-129. These structures reveal distinct binding pockets and interaction networks that dictate antagonist selectivity and efficacy. Notably, TG6-129 displays a novel binding mode, engaging deeply with EP2 while interacting more superficially with EP4 in a two-warhead manner. Furthermore, comparisons of active and inactive receptor structures elucidate the mechanisms underlying EP2 activation and antagonism. Overall, these findings provide a structural framework for understanding prostanoid receptor pharmacology and offer valuable insights for the rational design of improved selective and dual antagonists targeting EP2 and EP4 receptors. |
| WOS关键词 | CRYO-EM STRUCTURE ; POTENT |
| 资助项目 | Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Chinese Academy of Science Strategic Priority Research Program[XDB37030103] ; The National Key Research and Development Program of China[2022YFC2703105] ; The National Natural Science Foundation of China[32130022] ; The National Natural Science Foundation of China[82121005] ; The National Natural Science Foundation of China[32301016] ; Shanghai Post-doctoral Excellence Program[2023707] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001603559200001 |
| 出版者 | SPRINGERNATURE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/319711]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Wu, Yanli; Wu, Canrong; Xu, H. Eric |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Biliary Pancreat Surg, Shanghai 200025, Peoples R China 4.Shanghai Jiao Tong Univ, Ruijin Hosp,Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom,Sch Med, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Yanli,Zhang, Heng,Xu, Jiuyin,et al. Structural insights into selective and dual antagonism of EP2 and EP4 prostaglandin receptors[J]. EMBO JOURNAL,2025:21. |
| APA | Wu, Yanli.,Zhang, Heng.,Xu, Jiuyin.,Wu, Kai.,Hu, Wen.,...&Xu, H. Eric.(2025).Structural insights into selective and dual antagonism of EP2 and EP4 prostaglandin receptors.EMBO JOURNAL,21. |
| MLA | Wu, Yanli,et al."Structural insights into selective and dual antagonism of EP2 and EP4 prostaglandin receptors".EMBO JOURNAL (2025):21. |
入库方式： OAI收割
来源：上海药物研究所
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