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 (S1PRs) - S1P1-5. 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.

Structural basis for ligand recognition and signaling of the lysophosphatidylserine receptors GPR34 and GPR174

“…The binding modes of several other LPLs have been illustrated by previous structural studies, including LPA receptors [ 30 – 32 ], S1P receptors [ 33 – 39 ], and the LPC receptor GPR119 [ 40 ]. S1P receptors (S1P 1-5 ) are known as the endothelial differentiation gene (EDG) family.…”

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials

“…Most recently, another neuroprotective target sphingosine-1-phosphate receptor 5 (S1P 5 ) was focused and new clinical trial was initiated. S1P 5 is predominantly expressed in nervous system and playing a role in neurodegenerative disorders [ 218 ]. A phase 2 study of S1P 5 agonists ONO-2808 in patients with MSA is ongoing to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and potential efficacy as well (NCT05923866).…”

Sphingosine-1-Phosphate Signaling in Cardiovascular Diseases

“…The cryo-electron microscopy (cryo-EM) structures of the S1PR1-Gα i complex [32][33][34], S1PR2-Gα 13 complex [35], S1PR3-S1P complex [36], and S1PR5-Gα i /inverse agonist [37,38] have been resolved recently. Structural analyses suggested that the S1PR family possesses a highly conserved long channel shape of the orthosteric site and revealed conformational changes associated with activation and differences in ligand access.…”