Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate

Nat Commun. 2022 Feb 8;13(1):731. doi: 10.1038/s41467-022-28417-2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Azetidines / pharmacology
  • Azetidines / therapeutic use
  • Benzyl Compounds / pharmacology
  • Benzyl Compounds / therapeutic use
  • Cryoelectron Microscopy
  • GTP-Binding Protein alpha Subunits, Gi-Go / genetics
  • GTP-Binding Protein alpha Subunits, Gi-Go / isolation & purification
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • GTP-Binding Protein alpha Subunits, Gi-Go / ultrastructure
  • Humans
  • Lysophospholipids / metabolism
  • Molecular Conformation / drug effects
  • Molecular Docking Simulation
  • Multiple Sclerosis / drug therapy
  • Multiple Sclerosis / pathology
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / isolation & purification
  • Receptors, Lysophosphatidic Acid / metabolism*
  • Receptors, Lysophosphatidic Acid / ultrastructure
  • Recombinant Proteins / genetics
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / ultrastructure
  • Sf9 Cells
  • Single Molecule Imaging
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine-1-Phosphate Receptors / genetics
  • Sphingosine-1-Phosphate Receptors / isolation & purification
  • Sphingosine-1-Phosphate Receptors / metabolism*
  • Sphingosine-1-Phosphate Receptors / ultrastructure
  • Spodoptera

Substances

  • Azetidines
  • Benzyl Compounds
  • LPAR1 protein, human
  • Lysophospholipids
  • Receptors, Lysophosphatidic Acid
  • Recombinant Proteins
  • S1PR1 protein, human
  • Sphingosine-1-Phosphate Receptors
  • sphingosine 1-phosphate
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Sphingosine
  • lysophosphatidic acid
  • siponimod