GPR17: molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors.
GPR17: molecular modeling and dynamics studies of the 3-D structure and purinergic ligand binding features in comparison with P2Y receptors.
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GPR17：与P2Y受体相比，3-D结构和嘌呤能配体结合特征的分子建模和动力学研究。
DOI：
10.1186/1471-2105-9-263
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发表时间：
2008-06-04
影响因子：
3
通讯作者：
Fantucci, Piercarlo
中科院分区：
文献类型：
--
作者：
Parravicini, Chiara;Ranghino, Graziella;Abbracchio, Maria P.;Fantucci, Piercarlo
GPR 17是位于两个不同受体家族之间的中间系统发育位置的G蛋白偶联受体：分别用于细胞外核苷酸和半胱氨酰-LT的P2 Y和CysLT受体。我们以前表明，GPR 17确实可以响应两类内源性配体和合成化合物在上述受体家族的活性，从而代表了第一个完全表征的非肽“杂合”GPCR。在大鼠脑局灶性缺血模型中，通过反义技术或P2 Y/CysLT拮抗剂选择性地在体内敲低GPR 17减少了缺血性损伤的进展，从而突出了GPR 17作为中风的新治疗靶点。阐明GPR 17的结构和配体结合机制是获得针对该新的潜在靶点的选择性和有效药物的必要步骤。在此基础上，本研究的第一个目标是建立GPR 17嵌入溶剂化磷脂双层的三维分子模型，并通过分子动力学模拟进行优化。为了探索受体的“嘌呤能”组分的结合模式，然后对受体建模内源性激动剂UDP和两种证明对GPR 17有活性的P2 Y受体拮抗剂（MRS 2179和坎格雷洛）。分子动力学模拟表明，GPR 17核苷酸结合口袋是类似于其他P2 Y受体所描述的，虽然只有一个的三个基本的残基，通常参与配体识别是保守的（Arg 255）。结合袋被包围在螺旋束之间，并且在顶部被EL 2覆盖。驱动相互作用是6.55和6.52残基与配体的磷酸基团之间的氢键和盐桥。在由EL 2、EL 3和Nt形成的区域中还发现了“辅助”结合位点。与GPR 17结合的核苷酸发生在已知的P2 Y受体的相同受体区域上。激动剂/拮抗剂结合模式相似，但不相同。一个辅助的外部结合位点可以引导小的配体到更深的主要结合位点，在多步骤的激活机制。核苷酸结合口袋似乎不能以同样有效的方式分配白三烯型配体。
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. 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. 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.
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