GPR17: Molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors

Abstract

Background: GPR17 is a G-protein-coupled receptor located at intermediate phylogenetic position between two distinct receptor families: the P2Y and CysLT receptors for extracellular nucleotides and cysteinyl-LTs, respectively. We previously showed that GPR17 can indeed respond to both classes of endogenous ligands and to synthetic compounds active at the above receptor families, thus representing the first fully characterized non-peptide "hybrid" GPCR. In a rat brain focal ischemia model, the selective in vivo knock down of GPR17 by anti-sense technology or P2Y/ CysLT antagonists reduced progression of ischemic damage, thus highlighting GPR17 as a novel therapeutic target for stroke. Elucidation of the structure of GPR17 and of ligand binding mechanisms are the necessary steps to obtain selective and potent drugs for this new potential target. On this basis, a 3-D molecular model of GPR17 embedded in a solvated phospholipid bilayer and refined by molecular dynamics simulations has been the first aim of this study. To explore the binding mode of the "purinergic" component of the receptor, the endogenous agonist UDP and two P2Y receptor antagonists demonstrated to be active on GPR17 (MRS2179 and cangrelor) were then modeled on the receptor.

Is GPR17 a P2Y/Leukotriene Receptor? Examination of Uracil Nucleotides, Nucleotide Sugars, and Cysteinyl Leukotrienes as Agonists of GPR17

“…Although multiple follow-up studies consistent with this original report have been published by the same group (Parravicini et al, 2008;Pugliese et al, 2009;Buccioni et al, 2011;Daniele et al, 2011;Coppi et al, 2013), Benned-Jensen and Rosenkilde (2010) reported that UDP and UDP-glucose, but not cysteinyl leukotrienes, promoted GPR17-dependent guanosine 59-O-(3-[…”

Agonist-Induced Desensitization/Resensitization of Human G Protein-Coupled Receptor 17: A Functional Cross-Talk between Purinergic and Cysteinyl-Leukotriene Ligands

“…To verify if two distinct binding sites (one for nucleotides and the other for cysLTs) were present on GPR17 (Parravicini et al, 2008, the effects of the CysLT antagonist (montelukast) and the purinergic antagonist (cangrelor) were tested on the LTD 4 -and UDP-glucose-induced responses, respectively. Montelukast inhibited LTD 4 -mediated responses with an IC 50 value of 23.0 Ϯ 1.4 nM that was comparable with that from previous studies (Ciana et al, 2006).…”

“…One group has confirmed independently that GPR17 responds to purinergic uracil ligands (Benned-Jensen and Rosenkilde, 2010), whereas Maekawa et al (2009) have suggested GPR17 as a constitutive, negative regulator for CysLT 1 . Bioinformatic data have suggested the presence of two distinct binding sites on GPR17, one for nucleotides and the other for cysLT (Parravicini et al, 2008; however, it is still unclear if GPR17 predominantly behaves as a purinergic receptor that may be able to modulate responses to cysLTs through a protein-protein interaction mechanism.…”

The Regulated Expression, Intracellular Trafficking, and Membrane Recycling of the P2Y-like Receptor GPR17 in Oli-neu Oligodendroglial Cells

“…Recent work has led to the "deorphanization" of the G protein-coupled receptor (GPCR) 5 referred to as GPR17, which is located at an intermediate phylogenetic position between the purinergic P2Y receptors and the CysLT 1 and CysLT 2 receptors for cysteinyl-leukotrienes (cysLTs; [1][2][3][4][5][6]. Both recombinant and native GPR17 receptors respond to uracil nucleotides (e.g.…”