2. Academic Validation
  3. Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition

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

  • Cell Res. 2021 Dec;31(12):1263-1274. doi: 10.1038/s41422-021-00566-x.
Yuan Yuan # 1,  Guowen Jia # 1,  Chao Wu # 1,  Wei Wang # 1,  Lin Cheng 1,  Qian Li 1,  Ziyan Li 1,  Kaidong Luo 1,  Shengyong Yang 1,  Wei Yan 2 3,  Zhaoming Su 4 5,  Zhenhua Shao 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • 3 Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • 5 Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • 7 Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [email protected].
  • # Contributed equally.
PMID: 34526663 DOI: 10.1038/s41422-021-00566-x
Abstract

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.

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