Faculty Collaboration Database

Structural basis for receptor selectivity and inverse agonism in S1P₅ receptors. Nat Commun 2022 Aug 12;13(1):4736

Date

08/13/2022

Pubmed ID

35961984

Pubmed Central ID

PMC9374744

DOI

10.1038/s41467-022-32447-1

Scopus ID

2-s2.0-85135832975 (requires institutional sign-in at Scopus site)   6 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.

Author List

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

Author

Wei Liu PhD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Humans
Immune System
Lysophospholipids
Receptors, Lysosphingolipid
Sphingosine