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

<div class='caption-title'>Cryo-EM structures of the S1P–S1P1–Gi complex, the Siponimod–S1P1–Gi complex, and the LPA–LPA1–Gi complex.</div>
<div class='caption-title'>Interactions between S1P or Siponimod and S1P1.</div>
<div class='caption-title'>The orthosteric LPA-binding pocket of the active LPA1.</div>
Liu S, Paknejad N, Zhu L, Kihara Y, Ray M, Chun J, Liu W, Hite RK, Huang XY
OpenAccess logo Nat Commun 13 731 (2022)
Related entries: 7td0, 7td2, 7td3, 7td4

Cited: 37 times
EuropePMC logo PMID: 35136060

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.

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  1. The role of lipid metabolic reprogramming in tumor microenvironment. Yang K, Wang X, Song C, He Z, Wang R, Xu Y, Jiang G, Wan Y, Mei J, Mao W. Theranostics 13 1774-1808 (2023)
  2. G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery. Zhang M, Chen T, Lu X, Lan X, Chen Z, Lu S. Signal Transduct Target Ther 9 88 (2024)
  3. Sphingosine-1-Phosphate Signaling in Cardiovascular Diseases. Wang N, Li JY, Zeng B, Chen GL. Biomolecules 13 818 (2023)
  4. Molecular and neuroimmune pharmacology of S1P receptor modulators and other disease-modifying therapies for multiple sclerosis. Kihara Y, Chun J. Pharmacol Ther 246 108432 (2023)
  5. Involvement of Lysophospholipids in Pulmonary Vascular Functions and Diseases. Kume H, Harigane R, Rikimaru M. Biomedicines 12 124 (2024)

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