Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

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.; Okhrimenko, I.; Popov, P.; Hu, H.; Weierstall, U.; Liu, W.; Cho, Y.; Gushchin, I.; Rogachev, A.; Bourenkov, G.; Park, S.; Park, G.; Hyun, H. J.; Park, J.; Gordeliy, V.; Borshchevskiy, V.; Mishin, A.; Cherezov, V.

doi:10.1101/2022.02.25.480536

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bioRxiv · 10.1101/2022.02.25.480536

Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

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Abstract

The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PR) - 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 [A] 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 subpocket, 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, the new S1P5-inverse agonist structure sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR-family.

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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., Okhrimenko, I., Popov, P., Hu, H., Weierstall, U., Liu, W., Cho, Y., Gushchin, I., Rogachev, A., Bourenkov, G., Park, S., Park, G., Hyun, H. J., Park, J., Gordeliy, V., Borshchevskiy, V., Mishin, A., Cherezov, V.. 2022-02-26. Structural basis for receptor selectivity and inverse agonism in S1P5 receptors. https://doi.org/10.1101/2022.02.25.480536

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