Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate
Year: 2022
Type: article
Abstract: Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR–G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P1) and heterotrimeric Gi complexes formed with bound S1P or the multiple sclerosis (MS) treatment drug Siponimod, as well as human LPA receptor 1 (LPA1) and Gi complexes in the presence of LPA. Our structural and functional data provide insights into how LPA and S1P adopt different conformations to interact with their cognate GPCRs, the selectivity of the homologous lipid GPCRs for S1P versus LPA, and the different activation mechanisms of these GPCRs by LPA and S1P. Our studies also reveal specific optimization strategies to improve the MS-treating S1P1-targeting drugs.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,890
Awards: G2051006376, G2665966410, G289723095, G2911627494, G4102770861, Molecular characterization of the multi-modal regulation of inositol 1,4,5-trisphosphate receptors, G5387346438, G5850682332, S1P signaling machinery in neuroimmune interactions, G6294378553, G6403603385, Molecular Basis of B1-Adrenergic Receptor Function, G6539215626, Molecular Mechanisms of Apoptosis Regulation Through IP3 Receptors, G6570308026, Prenatal blood-borne lipids in post-hemorrhagic hydrocephalus, G8296034921, G8322667947, G9000003249, Cancer Center Support Grant
OpenAlex ID: W4210907760