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

Author

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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)

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.

Suggested Citation

  • Shian Liu & Navid Paknejad & Lan Zhu & Yasuyuki Kihara & Manisha Ray & Jerold Chun & Wei Liu & Richard K. Hite & Xin-Yun Huang, 2022. "Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28417-2
    DOI: 10.1038/s41467-022-28417-2
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    Cited by:

    1. Minfei Su & Jinan Wang & Guoqing Xiang & Hung Nguyen Do & Joshua Levitz & Yinglong Miao & Xin-Yun Huang, 2023. "Structural basis of agonist specificity of α1A-adrenergic receptor," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Xuan Zhang & Yujing Wang & Shreyas Supekar & Xu Cao & Jingkai Zhou & Jessica Dang & Siqi Chen & Laura Jenkins & Sara Marsango & Xiu Li & Guibing Liu & Graeme Milligan & Mingye Feng & Hao Fan & Weimin , 2023. "Pro-phagocytic function and structural basis of GPR84 signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Navid Paknejad & Vinay Sapuru & Richard K. Hite, 2023. "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Jiale Liang & Asuka Inoue & Tatsuya Ikuta & Ruixue Xia & Na Wang & Kouki Kawakami & Zhenmei Xu & Yu Qian & Xinyan Zhu & Anqi Zhang & Changyou Guo & Zhiwei Huang & Yuanzheng He, 2023. "Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    6. Tamaki Izume & Ryo Kawahara & Akiharu Uwamizu & Luying Chen & Shun Yaginuma & Jumpei Omi & Hiroki Kawana & Fengjue Hou & Fumiya K. Sano & Tatsuki Tanaka & Kazuhiro Kobayashi & Hiroyuki H. Okamoto & Yo, 2024. "Structural basis for lysophosphatidylserine recognition by GPR34," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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