Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

Elizaveta Lyapina, Egor Marin, Anastasiia Gusach, Philipp Orekhov, Andrey Gerasimov, Aleksandra Luginina, Daniil Vakhrameev, Margarita Ergasheva, Margarita Kovaleva, Georgii Khusainov, Polina Khorn, Mikhail Shevtsov, Kirill Kovalev, Sergey Bukhdruker, Ivan Okhrimenko, Petr Popov, Hao Hu, Uwe Weierstall, Wei Liu, Yunje Cho, Ivan Gushchin, Andrey Rogachev, Gleb Bourenkov, Sehan Park, Gisu Park, Hyo Jung Hyun, Jaehyun Park, Valentin Gordeliy, Valentin Borshchevskiy (), Alexey Mishin () and Vadim Cherezov ()
Additional contact information
Elizaveta Lyapina: Moscow Institute of Physics and Technology
Egor Marin: Moscow Institute of Physics and Technology
Anastasiia Gusach: Moscow Institute of Physics and Technology
Philipp Orekhov: Moscow Institute of Physics and Technology
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
Polina Khorn: Moscow Institute of Physics and Technology
Mikhail Shevtsov: Moscow Institute of Physics and Technology
Kirill Kovalev: Moscow Institute of Physics and Technology
Sergey Bukhdruker: Moscow Institute of Physics and Technology
Ivan Okhrimenko: Moscow Institute of Physics and Technology
Petr Popov: Moscow Institute of Physics 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
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
Valentin Gordeliy: Université Grenoble Alpes, CEA, CNRS
Valentin Borshchevskiy: Moscow Institute of Physics and Technology
Alexey Mishin: Moscow Institute of Physics and Technology
Vadim Cherezov: University of Southern California

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32447-1

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