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

Shian Liu, Navid Paknejad, Lan Zhu, Yasuyuki Kihara, Manisha Ray, Jerold Chun, Wei Liu, Richard K. Hite () and Xin-Yun Huang ()
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Shian Liu: Weill Cornell Medical College of Cornell University
Navid Paknejad: Memorial Sloan Kettering Cancer Center
Lan Zhu: Arizona State University
Yasuyuki Kihara: Sanford Burnham Prebys Medical Discovery Institute
Manisha Ray: Sanford Burnham Prebys Medical Discovery Institute
Jerold Chun: Sanford Burnham Prebys Medical Discovery Institute
Wei Liu: Arizona State University
Richard K. Hite: Memorial Sloan Kettering Cancer Center
Xin-Yun Huang: Weill Cornell Medical College of Cornell University

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28417-2

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