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; Vadim Cherezov

doi:10.1038/s41467-022-32447-1

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, Vadim Cherezov

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P_1-5. 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.

Original language	English (US)
Article number	4736
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32447-1
State	Published - Dec 2022
Externally published	Yes

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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10.1038/s41467-022-32447-1

Cite this

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), Article 4736. https://doi.org/10.1038/s41467-022-32447-1

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, Cho, Y, Gushchin, I, Rogachev, A, Bourenkov, G, Park, S, Park, G, Hyun, HJ, Park, J, Gordeliy, V, Borshchevskiy, V, Mishin, A & Cherezov, V 2022, 'Structural basis for receptor selectivity and inverse agonism in S1P₅ receptors', Nature communications, vol. 13, no. 1, 4736. https://doi.org/10.1038/s41467-022-32447-1

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title = "Structural basis for receptor selectivity and inverse agonism in S1P5 receptors",

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 {\AA} 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.",

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 Hyun, \{Hyo Jung\} and Jaehyun Park and Valentin Gordeliy and Valentin Borshchevskiy and Alexey Mishin and Vadim Cherezov",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-32447-1",

language = "English (US)",

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T1 - Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

AU - Lyapina, Elizaveta

AU - Marin, Egor

AU - Gusach, Anastasiia

AU - Orekhov, Philipp

AU - Gerasimov, Andrey

AU - Luginina, Aleksandra

AU - Vakhrameev, Daniil

AU - Ergasheva, Margarita

AU - Kovaleva, Margarita

AU - Khusainov, Georgii

AU - Khorn, Polina

AU - Shevtsov, Mikhail

AU - Kovalev, Kirill

AU - Bukhdruker, Sergey

AU - Okhrimenko, Ivan

AU - Popov, Petr

AU - Hu, Hao

AU - Weierstall, Uwe

AU - Liu, Wei

AU - Cho, Yunje

AU - Gushchin, Ivan

AU - Rogachev, Andrey

AU - Bourenkov, Gleb

AU - Park, Sehan

AU - Park, Gisu

AU - Hyun, Hyo Jung

AU - Park, Jaehyun

AU - Gordeliy, Valentin

AU - Borshchevskiy, Valentin

AU - Mishin, Alexey

AU - Cherezov, Vadim

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-022-32447-1

DO - 10.1038/s41467-022-32447-1

M3 - Article

C2 - 35961984

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4736

ER -

Structural basis for receptor selectivity and inverse agonism in S1P₅ receptors

Abstract

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