Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35136060.
- Also identified by DOI 10.1038/s41467-022-28417-2 and PMC identifier 8826421.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 (S1P<sub>1</sub>) and heterotrimeric G<sub>i</sub> complexes formed with bound S1P or the multiple sclerosis (MS) treatment drug Siponimod, as well as human LPA receptor 1 (LPA<sub>1</sub>) and G<sub>i</sub> 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 S1P<sub>1</sub>-targeting drugs.
Medical subject headings
- GTP-Binding Protein alpha Subunits, Gi-Go
- Receptors, Lysophosphatidic Acid
- Sphingosine-1-Phosphate Receptors