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.

1-磷酸鞘氨醇 (S1P) 是细胞膜代谢中重要的生物活性脂质分子，可与 G 蛋白偶联的 S1P 受体 (S1PRs) 结合以调节胚胎发育、生理稳态和各个器官的致病过程。S1PR 是脂质感应受体，是药物开发的治疗靶点，包括 COVID-19 的潜在治疗。在此，我们展示了与多种药物激动剂和异源三聚 Gi 蛋白结合的 S1PR 的五种低温电子显微镜结构。我们的结构和功能分析证明了 S1PRs 化学上不同的激动剂的不同结合模式，揭示了激活这些受体的机械开关，并为理解配体选择性和 G 蛋白偶联提供了框架。