7YXA

XFEL crystal structure of the human sphingosine 1 phosphate receptor 5 in complex with ONO-5430608

Summary for 7YXA

• Entry DOI: 10.2210/pdb7yxa/pdb
• Descriptor: Sphingosine 1-phosphate receptor 5,Soluble cytochrome b562, 2-acetamido-2-deoxy-beta-D-glucopyranose, 4-[6-(2-naphthalen-1-ylethoxy)-2,3,4,5-tetrahydro-1H-3-benzazepin-3-ium-3-yl]butanoic acid, ... (6 entities in total)
• Functional Keywords: gpcr, g-protein coupled receptor, xfel, x-ray free electron laser, serial femtosecond crystallography, sfx, sphingosine-1-phosphate, sphingosine-1-phosphate receptor, s1p5, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 102731.20

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.,Okhrimenko, I.,Bukhdruker, S.,Popov, P.,Hu, H.,Weierstall, U.,Liu, W.,Cho, Y.,Gushchin, I.,Rogachev, A.,Bourenkov, G.,Park, S.,Park, G.,Huyn, H.J.,Park, J.,Gordeliy, V.,Borshchevskiy, V.,Mishin, A.,Cherezov, V. (deposition date: 2022-02-15, release date: 2022-08-10, Last modification date: 2024-11-06)

Primary 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.,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.
Structural basis for receptor selectivity and inverse agonism in S1P 5 receptors.
Nat Commun, 13:4736-4736, 2022

PubMed Abstract: The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PRs) - S1P. S1P 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 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-inverse agonist sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR family.

PubMed: 35961984
DOI: 10.1038/s41467-022-32447-1

Experimental method

X-RAY DIFFRACTION (2.2 Å)