Structural basis for receptor selectivity and inverse agonism in S1P5 receptors
Open accessPublished version of a preprint
Abstract
The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P 1-5 . S1P 5 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 S1P 5 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 S1P 5 -inverse agonist sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR family.
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- Authors
- 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, H. J., Park, J., Gordeliy, V., Borshchevskiy, V., Mishin, A., & Cherezov, V.
- Affiliations
- Moscow Institute of Physics and Technology (RU)
- Vyatka State University (RU)
- Skolkovo Institute of Science and Technology (RU)
- Arizona State University (US)
- Medical College of Wisconsin (US)
- Pohang University of Science and Technology (KR)
- European Molecular Biology Laboratory (DE)
- Centre National de la Recherche Scientifique (FR)
- University of Southern California (US)
- Corresponding author
- Borshchevskiy, Valentin
- Mishin, Alexey
- Cherezov, Vadim
- ORCID
- Lyapina, Elizaveta
- Marin, Egor
- Gusach, Anastasiia
- Orekhov, Philipp
- Gerasimov, Andrey
- Luginina, Aleksandra
- Vakhrameev, Daniil
- Kovaleva, Margarita
- Khusainov, Georgii
- Khorn, Polina
- Shevtsov, Mikhail
- Kovalev, Kirill
- Bukhdruker, Sergey
- Okhrimenko, Ivan
- Popov, Petr
- Hu, Hao
- Weierstall, Uwe
- Liu, Wei
- Cho, Yunje
- Gushchin, Ivan
- Rogachev, Andrey
- Bourenkov, Gleb
- Park, Sehan
- Park, Gisu
- Park, Jaehyun
- Gordeliy, Valentin
- Borshchevskiy, Valentin
- Mishin, Alexey
- Cherezov, Vadim
- Venue
- Nature Communications
- Published
- 2022-08-12
- Volume
- 13
- Issue
- 1
- Pages
- 4736-4736
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9374744
- OpenAlex
- W4290839367
- Cited by
- 26
- References
- 4
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 5 · 2023: 5 · 2022: 3
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Funders
- Russian Science Foundation (22-74-10036, 22-24-00454, 20-24-00454)
- Russian Foundation for Basic Research (18-02-40020)
- National Research Foundation of Korea (NRF-2017M3A9F6029736)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- sphingosine-1-phosphate, inverse agonism, receptor subtype selectivity, ligand binding modes, structure-activity relationship, structure-based drug design, receptor activation mechanism
- MeSH terms
- Humans, Immune System, Lysophospholipids, Sphingosine, Receptors, Lysosphingolipid
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