期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32447-1
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资金
- Ministry of Science and Higher Education of the Russian Federation [075-00337-20-03, FSMG-2020-0003]
- Russian Ministry of Science and Higher Education [075-15-2021-1354]
- Russian Foundation for Basic Research (RFBR) project [18-02-40020]
- Russian Science Foundation [22-74-10036, 22-24-00454]
- National Research Foundation of Korea [NRF-2017M3A9F6029736]
- National Science Foundation (NSF) BioXFEL Science and Technology Center award [1231306]
- Advancing Healthier Wisconsin Endowment (AHW) fund
This study reports the crystal structure of the S1P(5) receptor in complex with a selective inverse agonist, revealing an allosteric subpocket and shedding light on inverse agonism in S1P receptors.
S1P(5) is a sphingosine-1-phosphate (S1P) receptor implicated in immune and neurodegenerative disorders. Here, authors report a crystal structure of the S1P(5) receptor in complex with a selective inverse agonist, revealing an allosteric subpocket and shedding light on inverse agonism in S1P receptors. 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 A 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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