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

<p>Abstract</p> <p>Background</p> <p>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 <it>in vivo </it>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.</p> <p>Results</p> <p>Molecular dynamics simulations suggest that GPR17 nucleotide binding pocket is similar to that described for the other P2Y receptors, although only one of the three basic residues that have been typically involved in ligand recognition is conserved (Arg255). The binding pocket is enclosed between the helical bundle and covered at the top by EL2. Driving interactions are H-bonds and salt bridges between the 6.55 and 6.52 residues and the phosphate moieties of the ligands. An "accessory" binding site in a region formed by the EL2, EL3 and the Nt was also found.</p> <p>Conclusion</p> <p>Nucleotide binding to GPR17 occurs on the same receptor regions identified for already known P2Y receptors. Agonist/antagonist binding mode are similar, but not identical. An accessory external binding site could guide small ligands to the deeper principal binding site in a multi-step mechanism of activation. The nucleotide binding pocket appears to be unable to allocate the leukotrienic type ligands in the same effective way.</p

The computational-based structure of Dwarf14 provides evidence for its role as potential strigolactone receptor in plants

Abstract Background Strigolactones (SLs) are recently identified plant hormones modulating root and shoot branching. Besides their endogenous role within the producing organism, SLs are also key molecules in the communication of plants with arbuscular mycorrhizal (AM) fungi and parasitic weeds. In fact SLs are exuded into the rhizosphere where they act as a host-derived signal, stimulating the germination of the seeds of parasitic plants which would not survive in the absence of a host root to colonize. Similarly, their perception by AM fungi causes extensive hyphal branching; this is a prerequisite for effective root colonization, since it increases the number of potential contact points with the host surface. In spite of the crucial and multifaceted biological role of SLs, there is no information on the receptor(s) which bind(s) such active molecules, neither in the producing plants, or in parasitic weeds or AM fungi. Results In this work, we applied homology modelling techniques to investigate the structure of the protein encoded by the gene Dwarf14, which was first identified in rice as conferring SLs insensitivity when mutated. The best sequence identity was with bacterial RsbQ. Both proteins belong to the superfamily of alpha/beta-fold hydrolases, some members of which play a role in the metabolism or signalling of plant hormones. The Dwarf14 (D14) structure was refined by means of molecular dynamics simulations. In order to support the hypothesis that D14 could be an endogenous SLs receptor, we performed docking experiments with a natural ligand. Conclusions It is suggested that D14 interacts with and thereby may act as a receptor for SLs in plants. This hypothesis offers a starting point to experimentally study the mechanism of its activity in vivo by means of structural, molecular and genetic approaches. Lastly, knowledge of the putative receptor structure will boost the research on analogues of the natural substrates as required for agricultural applications.</p

GPR17: Molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors-2

.<p><b>Copyright information:</b></p><p>Taken from "GPR17: Molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors"</p><p>http://www.biomedcentral.com/1471-2105/9/263</p><p>BMC Bioinformatics 2008;9():263-263.</p><p>Published online 4 Jun 2008</p><p>PMCID:PMC2443813.</p><p></p

GPR17: Molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors-7

1 (TM3); Cys23 (Nt) and Cys269 (EL3) form an additional disulphide bridge that seems to be a peculiar feature of a restricted subgroup of GPCRs among which GPR17, P2Y and CysLT receptors. See supplementary material for the full alignment.<p><b>Copyright information:</b></p><p>Taken from "GPR17: Molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors"</p><p>http://www.biomedcentral.com/1471-2105/9/263</p><p>BMC Bioinformatics 2008;9():263-263.</p><p>Published online 4 Jun 2008</p><p>PMCID:PMC2443813.</p><p></p