Structural insights into sphingosine-1-phosphate receptor activation

Significance Sphingosine-1-phosphate (S1P) receptors are valid therapeutic targets to treat autoimmune diseases, such as relapsing multiple sclerosis and ulcerative colitis. Particularly, S1PR1 is well characterized because of its nonredundant functions on T and B cells’ egress. However, the activation mechanism of S1PR1 is still poorly understood. Therefore, we determined active S1PR1–Gi complex structures bound to distinct agonists. Phosphorylated Fingolimod [(S)-FTY720-P] could modulate lymphocyte trafficking and treat multiple sclerosis. The nonlipid-like agonist CBP-307 is currently being evaluated in a global phase 2 clinical study in moderate to severe ulcerative colitis and Crohn’s disease. Meanwhile, two binding poses of CBP-307 and the unoccupied subpocket we observed may provide opportunities to improve further the efficacy and specificity of CBP-307 targeting different S1P receptors.