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Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

By Elizaveta Lyapina, Egor Marin1, 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 Weierstall2, Wei Liu2, Yunje Cho, Ivan Gushchin, Andrey Rogachev, Gleb Bourenkov, Sehan Park, Gisu Park, Hyo Jung Hyun, Jaehyun Park, Valentin Gordeliy, Valentin Borshchevskiy, Alexey Mishin, Vadim Cherezov3

1. Moscow Institute of Physics and Technology 2. Arizona State University 3. Bridge Institute - University of Southern California

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Category

BioXFEL Publications

Published on

Type

journal-article

Author

Elizaveta Lyapina and Egor Marin and Anastasiia Gusach and Philipp Orekhov and Andrey Gerasimov and Aleksandra Luginina and Daniil Vakhrameev and Margarita Ergasheva and Margarita Kovaleva and Georgii Khusainov and Polina Khorn and Mikhail Shevtsov and Kirill Kovalev and Sergey Bukhdruker and Ivan Okhrimenko and Petr Popov and Hao Hu and Uwe Weierstall and Wei Liu and Yunje Cho and Ivan Gushchin and Andrey Rogachev and Gleb Bourenkov and Sehan Park and Gisu Park and Hyo Jung Hyun and Jaehyun Park and Valentin Gordeliy and Valentin Borshchevskiy and Alexey Mishin and Vadim Cherezov

Citation

Lyapina, E., Marin, E., Gusach, A., Orekhov, P., Gerasimov, A., Luginina, A., Vakhrameev, D., Ergasheva, M., Kovaleva, M., Khusainov, G., Khorn, P., Shevtsov, M., Kovalev, K., Bukhdruker, S., Okhrimenko, I., Popov, P., Hu, H., Weierstall, U., Liu, W., … Cherezov, V. (2022). Structural basis for receptor selectivity and inverse agonism in S1P5 receptors. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-32447-1

Abstract

AbstractThe 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.

DOI

http://dx.doi.org/10.1038/s41467-022-32447-1

Funding

NSF-STC Biology with X-ray Lasers (NSF-1231306)