Structural Biology of the S1P1 Receptor

Abstract

The sphingosine 1 phosphate receptor family has been studied widely since the initial discovery of its first member, endothelium differentiation gene 1. Since this initial discovery, the family has been renamed and the primary member of the family, the S1P1 receptor, has been targeted for a variety of disease indications and successfully drugged for the treatment of patients with relapsing multiple sclerosis. Recently, the three-dimensional structure of the S1P1 receptor has been determined by X-ray crystallography and the specifics of the sphingosine 1 phosphate ligand binding pocket mapped. Key structural features for the S1P1 receptor will be reviewed and the potential binding modes of additional pharmacologically active agents against the receptor will be analyzed in an effort to better understand the structural basis of important receptor-ligand interactions.

HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner

“…SR-B1 is known to mediate the cellular uptake of diverse HDL-bound lipids (49), and homology modeling of the three-dimensional structure of SR-B1 suggests the presence of a hydrophobic channel extending from the HDL-binding site to the membrane (35). The crystal structure of at least one S1P receptor, S1PR 1 , suggests that the binding site for S1P is embedded within the membrane (18,19). This suggests that SR-B1's role in HDLmediated survival signaling in cardiomyocytes and other cells may be to mediate the transfer of S1P from the bound HDL particle into the membrane, where it can access the S1Pbinding site on S1P receptors.…”

ST-2191, an Anellated Bismorpholino Derivative of Oxy-Fingolimod, Shows Selective S1P1 Agonist and Functional Antagonist Potency In Vitro and In Vivo

“…Furthermore, ST-2191, which is an anellated bismorpholino derivative by the formal condensation of two morpholine rings, i.e., perhydro[1,4]oxazino[3,4-c][1,4]oxazine derivative of oxy-fingolimod, strongly resembles the oxazolo-oxazolo derivative ST-1071 [ 20 ], but contains a larger polar head group. The trigger for agonism on the S1P 1 receptor is associated with an increase in binding pocket volume and ligands with larger volume can have a more hampered dissociation, which could lead to higher activity [ 18 , 27 ]. However, it seems that there is a limitation to the volume of the ligand that can be accommodated in the binding pocket.…”

S12

“…To date, five S1P receptors EDG1/S1P 1 , EDG5/ S1P 2 , EDG3/S1P 3 , EDG6/S1P 4 , and EDG8/S1P 5 that bind to S1P and dihydro-S1P have been identified in vertebrates (Hanson and Peach 2014). In mammalian cells, S1PRs are ubiquitous, but their expression patterns vary among the different tissues.…”