Structural basis for receptor selectivity and inverse agonism in S1P₅ receptors

Abstract

The bioactive lysophospholipid sphingosine-1-phosphate (S1P) acts via five different subtypes of S1P receptors (S1PR) - S1P1-5. S1P5is 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 S1P5receptor 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 subpocket, 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, the new S1P5-inverse agonist structure sheds light on the activation mechanism and reveals structural determinants of the inverse agonism in the S1PR-family.

Overview of lipid-sensing GPCR receptors structure and function

“…Methods: X-Ray Crystallography at microfocus beamlines of synchrotron sources and X-Ray Free Electron Lasers combined with functional assays, structure-activity relationship studies, molecular modeling and docking. Results: In this report we will discuss the structural and functional peculiarities of lipidsensing GPCRs, including the three representatives, for which the structure was recently obtained by our team: CysLT1 [1], CysLT2 [2], S1P5 [3]. Conclusions: Further complex structural and functional studies of lipid-sensing receptors need to be carried out to find answers to fundamental questions about the molecular mechanisms of their functioning and the rational creation of drugs.…”