Volume 31, No 12, Dec 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 12, December 2021: 1263-1274

ORIGINAL ARTICLES

Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition

Yuan Yuan^1,† , Guowen Jia^1,† , Chao Wu^1,† , Wei Wang^1,† , Lin Cheng¹ , Qian Li¹ , Ziyan Li¹ , Kaidong Luo¹ , Shengyong Yang¹ , Wei Yan^1,2,* , Zhaoming Su^1,3,* , Zhenhua Shao^1,2,*

¹State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
²Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
³Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
^†These authors contributed equally: Yuan Yuan, Guowen Jia, Chao Wu, Wei Wang
Correspondence: Wei Yan(weiyan2018@scu.edu.cn)Zhaoming Su(zsu@scu.edu.cn)Zhenhua Shao(zhenhuashao@scu.edu.cn)

Sphingosine-1-phosphate (S1P) is an important bioactive lipid molecule in cell membrane metabolism and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, physiological homeostasis, and pathogenic processes in various organs. S1PRs are lipid-sensing receptors and are therapeutic targets for drug development, including potential treatment of COVID-19. Herein, we present five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. Our structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling.gical homeostasis, and pathogenic processes in various organs. S1PRs are lipid-sensing receptors and are therapeutic targets for drug development, including potential treatment of COVID-19. Herein, we present five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. Our structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling.

https://doi.org/10.1038/s41422-021-00566-x

FULL TEXT | PDF

Browse 427