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.
Original language | English (US) |
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Article number | 731 |
Journal | Nature communications |
Volume | 13 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2022 |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General
- General Physics and Astronomy
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Dive into the research topics of 'Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate'. Together they form a unique fingerprint.Datasets
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Lysophosphatidic acid receptor 1-Gi complex bound to LPA, state a
Liu, S. (Contributor), Paknejad, N. (Contributor), Zhu, L. (Contributor), Kihara, Y. (Contributor), Ray, M. (Contributor), Chun, J. (Contributor), Liu, W. (Contributor), Hite, R. K. (Contributor) & Huang, X. (Contributor), Protein Data Bank (PDB), Feb 9 2022
DOI: 10.2210/pdb7TD1, https://www.wwpdb.org/pdb?id=pdb_00007td1
Dataset
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Lysophosphatidic acid receptor 1-Gi complex bound to LPA
Liu, S. (Contributor), Paknejad, N. (Contributor), Zhu, L. (Contributor), Kihara, Y. (Contributor), Ray, M. (Contributor), Chun, J. (Contributor), Liu, W. (Contributor), Hite, R. K. (Contributor) & Huang, X. (Contributor), Protein Data Bank (PDB), Feb 9 2022
DOI: 10.2210/pdb7TD0, https://www.wwpdb.org/pdb?id=pdb_00007td0
Dataset
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Lysophosphatidic acid receptor 1-Gi complex bound to LPA, state a
Liu, S. (Contributor), Paknejad, N. (Contributor), Zhu, L. (Contributor), Kihara, Y. (Contributor), Ray, M. (Contributor), Chun, J. (Contributor), Liu, W. (Contributor), Hite, R. K. (Contributor) & Huang, X. (Contributor), Protein Data Bank (PDB), Feb 9 2022
DOI: 10.2210/pdb7TD2, https://www.wwpdb.org/pdb?id=pdb_00007td2
Dataset