Liu et al. report structures of human sphingosine 1-phosphate (S1P) receptor 1 (S1P1) in complex with Gi and S1P or the multiple sclerosis (MS) drug Siponimod, as well as human lysophosphatidic acid (LPA) receptor 1 (LPA1) in complex with Gi and LPA, revealing distinct conformations of the lysophospholipids interacting with their cognate GPCRs. This evidence concerns the gene GNAI1 and myeloid sarcoma.