Structural basis for receptor selectivity and inverse agonism in S1P5 receptors PMID: 35961984

ADC Targets in Oncology

2026-04-10

Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

Nat Commun. 2022 Aug 12;13(1):4736. doi: 10.1038/s41467-022-32447-1.

Elizaveta Lyapina ^# ¹ , Egor Marin ^# ¹ ² , Anastasiia Gusach ^# ¹ ³ , Philipp Orekhov ¹ ⁴ ⁵ , Andrey Gerasimov ⁶ , Aleksandra Luginina ¹ , Daniil Vakhrameev ¹ , Margarita Ergasheva ¹ , Margarita Kovaleva ¹ , Georgii Khusainov ¹ ⁷ , Polina Khorn ¹ , Mikhail Shevtsov ¹ , Kirill Kovalev ¹ ⁸ , Sergey Bukhdruker ¹ , Ivan Okhrimenko ¹ , Petr Popov ¹ ⁹ , Hao Hu ¹⁰ , Uwe Weierstall ¹⁰ , Wei Liu ¹¹ , Yunje Cho ¹² , Ivan Gushchin ¹ , Andrey Rogachev ¹ ¹³ , Gleb Bourenkov ⁸ , Sehan Park ¹⁴ , Gisu Park ¹⁴ , Hyo Jung Hyun ¹⁴ , Jaehyun Park ¹⁴ ¹⁵ , Valentin Gordeliy ¹⁶ , Valentin Borshchevskiy ¹⁷ ¹⁸ , Alexey Mishin ¹⁹ , Vadim Cherezov ²⁰

Affiliations

1. Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia.
2. Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
3. MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK.
4. Faculty of Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.
5. Faculty of Biology, Shenzhen MSU-BIT University, Shenzhen, 518172, China.
6. Vyatka State University, Kirov, 610020, Russia.
7. Division of Biology and Chemistry, Paul Scherrer Institute, Forschungsstrasse 111, 5232, Villigen, PSI, Switzerland.
8. European Molecular Biology Laboratory, Hamburg unit c/o DESY, Hamburg, Germany.
9. iMolecule, Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, bld. 1, Moscow, 121205, Russia.
10. Department of Physics, Arizona State University, Tempe, AZ, 85281, USA.
11. Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
12. Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
13. Joint Institute for Nuclear Research, Dubna, 141980, Russia.
14. Pohang Accelerator Laboratory, POSTECH, Pohang, 37673, Republic of Korea.
15. Department of Chemical Engineering, POSTECH, Pohang, 37673, Republic of Korea.
16. Institut de Biologie Structurale (IBS), Université Grenoble Alpes, CEA, CNRS, Grenoble, 38400, France.
17. Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia. [email protected].
18. Joint Institute for Nuclear Research, Dubna, 141980, Russia. [email protected].
19. Research Сenter for Molecular Mechanisms of Aging and Age-related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia. [email protected].
20. Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA. [email protected].
# Contributed equally.

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.