Abstract
The sphingosine-1-phosphate receptor 1 (S1P1), originally the endothelial differentiation gene 1 receptor (EDG-1), is one of five G protein–coupled receptors (GPCRs) S1P1–5 that bind to and are activated by sphingosine-1-phosphate (S1P). The lipid S1P is an intermediate in sphingolipid homeostasis, and S1P1 is a major medical target for immune system modulation; agonism of the receptor produces a myriad of biological responses, including endothelial cell barrier integrity, chemotaxis, lymphocyte trafficking/targeting, angiogenesis, as well as regulation of the cardiovascular system. Use of in silico docking simulations on the crystal structure of S1P1 allows for pinpointing the residues within the receptor’s active site that actively contribute to the binding of S1P, and point to how these specific interactions can be exploited to design more effective synthetic analogs to specifically target S1P1 in the presence of the closely related receptors S1P2, S1P3, S1P4, and S1P5. We examined the binding properties of the endogenous substrate as well as a selection of synthetic sphingosine-derived S1P1 modulators of S1P1 with in silico docking simulations using the software package Molecular Operating Environment® (MOE®). The modeling studies reveal the relevance of phosphorylation, i.e., the presence of a phosphate or phosphonate moiety within the substrate for successful binding to occur, and indicate which residues are responsible for S1P1 binding of the most prominent sphingosine-1-phosphate receptor (S1PR) modulators, including fingolimod and its structural relatives. Furthermore, trends in steric preferences as for the binding of enantiomers to S1P1 could be observed, facilitating future design of receptor-specific substrates to precisely target the active site of S1P1.
Highlights
With over 800 types encoded alone in the human genome, G protein–coupled receptors (GPCRs) constitute the largest family of 7-transmembrane (7TM) domain receptors ubiquitously expressed in all eukaryotic organisms and are responsible for numerous biological processes as intercellular signaling gateways (Pierce et al, 2002; Fredriksson et al, 2003)
Termed the endothelial differentiation gene (EDG), sphingosine-1-phosphate receptor (S1PR) class GPCRs rely on the phosphorylated sphingoid base sphingosine-1-phosphate (S1P) for agonism, and are involved in a multitude of pathophysiological processes as they regulate cellular barrier integrity, differentiation and proliferation, cell migration, angiogenesis, as well as immunity
The crystal structure of sphingosine-1-phosphate receptor 1 (S1P1) was obtained from the Protein Data Bank (PDB) file 3V2Y, giving the structure of S1P1 bound to the antagonist ML056 (W146, Table 1) at 2.8 Å resolution, as reported by Hanson et al (2012)
Summary
With over 800 types encoded alone in the human genome, G protein–coupled receptors (GPCRs) constitute the largest family of 7-transmembrane (7TM) domain receptors ubiquitously expressed in all eukaryotic organisms and are responsible for numerous biological processes as intercellular signaling gateways (Pierce et al, 2002; Fredriksson et al, 2003). S1P1 Agonists (Garcia et al, 2001; Matloubian et al, 2004; Spiegel and Weinstein, 2004; Heng et al, 2013; Bigaud et al, 2014; Camp et al, 2020) This involvement with diverse diseases and syndromes makes GPCRs a major medicinal drug target with approximately 40% of all therapeutic agents being developed to target this class of receptors (Hauser et al, 2017; Santos et al, 2017). Of the five known types of S1PRs (S1P1−5), S1P1 (EDG-1) is of particular interest since it has been shown to be the primary vascular barrier-regulatory receptor (Garcia et al, 2001; Dudek et al, 2004; McVerry et al, 2004; Peng et al, 2004; Sammani et al, 2010). The successful co-crystallization of S1P1 bound to the synthetic antagonist ML056 (W146) by Hanson et al (2012) has allowed access to the crystal structure of S1P1 for in silico analyses of the binding behavior of known, as well as novel substrates within the active site of the receptor (Hanson et al, 2012)
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