2. Academic Validation
  3. 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

  • Sci Adv. 2021 Apr 2;7(14):eabf1268. doi: 10.1126/sciadv.abf1268.
Changxiu Qu 1 2,  Chunyou Mao 3 4,  Peng Xiao 2,  Qingya Shen 3 4,  Ya-Ni Zhong 2,  Fan Yang 2,  Dan-Dan Shen 3 4,  Xiaona Tao 2,  Huibing Zhang 3 4,  Xu Yan 2 5,  Ru-Jia Zhao 2,  Junyan He 2,  Ying Guan 2,  Chao Zhang 6,  Guihua Hou 6,  Peng-Ju Zhang 2,  Guige Hou 7,  Zijian Li 8,  Xiao Yu 5,  Ren-Jie Chai 9,  You-Fei Guan 10,  Jin-Peng Sun 11 2,  Yan Zhang 12 4 13 14
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
  • 2 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo college of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 3 Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
  • 4 Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China.
  • 5 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 6 Biomedical Isotope Research Center, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 7 School of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, China.
  • 8 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Research, Beijing 100191, China.
  • 9 State Key Laboratory of Bioelectronics, Co-Innovation Center of Neuroregeneration, School of Life Sciences and Technology, Southeast University, Nanjing 210096, China. [email protected] [email protected] [email protected].
  • 10 Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
  • 11 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. [email protected] [email protected] [email protected].
  • 12 Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China. [email protected] [email protected] [email protected].
  • 13 MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 14 Zhejiang Provincial Key Laboratory of Immunity and Inflammatory Diseases, Hangzhou 310058, China.
PMID: 33811074 DOI: 10.1126/sciadv.abf1268
Abstract

Selective modulation of the heterotrimeric G protein α S subunit-coupled prostaglandin E2 (PGE2) 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-Gs complex with its endogenous agonist PGE2 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 W6.48 "toggle switch" and coupling to Gs 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 PGE2 signaling system.

Figures
Products