Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate. Nat Commun 2022 Feb 08;13(1):731
Date
02/10/2022Pubmed ID
35136060Pubmed Central ID
PMC8826421DOI
10.1038/s41467-022-28417-2Scopus ID
2-s2.0-85124279039 (requires institutional sign-in at Scopus site) 39 CitationsAbstract
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.
Author List
Liu S, Paknejad N, Zhu L, Kihara Y, Ray M, Chun J, Liu W, Hite RK, Huang XYAuthors
Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of WisconsinLan Zhu PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAzetidines
Benzyl Compounds
Cryoelectron Microscopy
GTP-Binding Protein alpha Subunits, Gi-Go
Humans
Lysophospholipids
Molecular Conformation
Molecular Docking Simulation
Multiple Sclerosis
Receptors, Lysophosphatidic Acid
Recombinant Proteins
Sf9 Cells
Single Molecule Imaging
Sphingosine
Spodoptera
