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

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...

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Bibliographic Details
Published in:Cell research 2021-12, Vol.31 (12), p.1263-1274
Main Authors: Yuan, Yuan, Jia, Guowen, Wu, Chao, Wang, Wei, Cheng, Lin, Li, Qian, Li, Ziyan, Luo, Kaidong, Yang, Shengyong, Yan, Wei, Su, Zhaoming, Shao, Zhenhua
Format: Article
Language:English
Subjects:
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631/535/1258/1259
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Agonists
Azetidines - chemistry
Azetidines - metabolism
Benzyl Compounds - chemistry
Benzyl Compounds - metabolism
Biomedical and Life Sciences
Cell Biology
Cell membranes
COVID-19
Cryoelectron Microscopy
Drug development
Electron microscopy
Embryogenesis
Embryonic growth stage
G protein-coupled receptors
Homeostasis
Humans
Life Sciences
Lipids
Molecular Dynamics Simulation
Organs
Protein Binding
Protein Structure, Quaternary
Protein turnover
Proteins
Receptors
Selectivity
Signal Transduction
Sphingosine 1-phosphate
Sphingosine-1-Phosphate Receptors - agonists
Sphingosine-1-Phosphate Receptors - genetics
Sphingosine-1-Phosphate Receptors - metabolism
Structure-function relationships
Therapeutic targets
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Summary: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.
ISSN:1001-0602
1748-7838
DOI:10.1038/s41422-021-00566-x