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Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

Author

Listed:
  • Elizaveta Lyapina

    (Moscow Institute of Physics and Technology)

  • Egor Marin

    (Moscow Institute of Physics and Technology
    University of Groningen)

  • Anastasiia Gusach

    (Moscow Institute of Physics and Technology
    MRC Laboratory of Molecular Biology)

  • Philipp Orekhov

    (Moscow Institute of Physics and Technology
    Lomonosov Moscow State University
    Shenzhen MSU-BIT University)

  • Andrey Gerasimov

    (Vyatka State University)

  • Aleksandra Luginina

    (Moscow Institute of Physics and Technology)

  • Daniil Vakhrameev

    (Moscow Institute of Physics and Technology)

  • Margarita Ergasheva

    (Moscow Institute of Physics and Technology)

  • Margarita Kovaleva

    (Moscow Institute of Physics and Technology)

  • Georgii Khusainov

    (Moscow Institute of Physics and Technology
    Paul Scherrer Institute)

  • Polina Khorn

    (Moscow Institute of Physics and Technology)

  • Mikhail Shevtsov

    (Moscow Institute of Physics and Technology)

  • Kirill Kovalev

    (Moscow Institute of Physics and Technology
    Hamburg unit c/o DESY)

  • Sergey Bukhdruker

    (Moscow Institute of Physics and Technology)

  • Ivan Okhrimenko

    (Moscow Institute of Physics and Technology)

  • Petr Popov

    (Moscow Institute of Physics and Technology
    iMolecule, Skolkovo Institute of Science and Technology)

  • Hao Hu

    (Arizona State University)

  • Uwe Weierstall

    (Arizona State University)

  • Wei Liu

    (Medical College of Wisconsin)

  • Yunje Cho

    (Pohang University of Science and Technology)

  • Ivan Gushchin

    (Moscow Institute of Physics and Technology)

  • Andrey Rogachev

    (Moscow Institute of Physics and Technology
    Joint Institute for Nuclear Research)

  • Gleb Bourenkov

    (Hamburg unit c/o DESY)

  • Sehan Park

    (Pohang Accelerator Laboratory, POSTECH)

  • Gisu Park

    (Pohang Accelerator Laboratory, POSTECH)

  • Hyo Jung Hyun

    (Pohang Accelerator Laboratory, POSTECH)

  • Jaehyun Park

    (Pohang Accelerator Laboratory, POSTECH
    Department of Chemical Engineering, POSTECH)

  • Valentin Gordeliy

    (Université Grenoble Alpes, CEA, CNRS)

  • Valentin Borshchevskiy

    (Moscow Institute of Physics and Technology
    Joint Institute for Nuclear Research)

  • Alexey Mishin

    (Moscow Institute of Physics and Technology)

  • Vadim Cherezov

    (University of Southern California)

Abstract

The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P1-5. S1P5 is predominantly expressed in nervous and immune systems, regulating the egress of natural killer cells from lymph nodes and playing a role in immune and neurodegenerative disorders, as well as carcinogenesis. Several S1PR therapeutic drugs have been developed to treat these diseases; however, they lack receptor subtype selectivity, which leads to side effects. In this article, we describe a 2.2 Å resolution room temperature crystal structure of the human S1P5 receptor in complex with a selective inverse agonist determined by serial femtosecond crystallography (SFX) at the Pohang Accelerator Laboratory X-Ray Free Electron Laser (PAL-XFEL) and analyze its structure-activity relationship data. The structure demonstrates a unique ligand-binding mode, involving an allosteric sub-pocket, which clarifies the receptor subtype selectivity and provides a template for structure-based drug design. Together with previously published S1PR structures in complex with antagonists and agonists, our structure with S1P5-inverse agonist sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR family.

Suggested Citation

  • Elizaveta Lyapina & Egor Marin & Anastasiia Gusach & Philipp Orekhov & Andrey Gerasimov & Aleksandra Luginina & Daniil Vakhrameev & Margarita Ergasheva & Margarita Kovaleva & Georgii Khusainov & Polin, 2022. "Structural basis for receptor selectivity and inverse agonism in S1P5 receptors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32447-1
    DOI: 10.1038/s41467-022-32447-1
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    References listed on IDEAS

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