Prediction of the 3D Structure and Dynamics of Human DP G-Protein Coupled Receptor Bound to an Agonist and an Antagonist
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- 作者：Youyong Li ; Fangqiang Zhu ; Nagarajan Vaidehi ; William A. Goddard ; III ; Felix Sheinerman ; Stephan Reiling ; Isabelle Morize ; Lan Mu ; Keith Harris ; Ali Ardati ; Abdelazize Laoui
- 刊名：Journal of the American Chemical Society
- 出版年：2007
- 出版时间：September 5, 2007
- 年：2007
- 卷：129
- 期：35
- 页码：10720 - 10731
- 全文大小：1071K
- 年卷期：v.129,no.35(September 5, 2007)
- ISSN：1520-5126
文摘
Prostanoids play important physiological roles in the cardiovascular and immune systems andin pain sensation in peripheral systems through their interactions with eight G-protein coupled receptors.These receptors are important drug targets, but development of subtype specific agonists and antagonistshas been hampered by the lack of 3D structures for these receptors. We report here the 3D structure forthe human DP G-protein coupled receptor (GPCR) predicted by the MembStruk computational method.To validate this structure, we use the HierDock computational method to predict the binding mode for theendogenous agonist (PGD2) to DP. Based on our structure, we predicted the binding of different antagonistsand optimized them. We find that PGD2 binds vertically to DP in the TM1237 region with the 
chaintoward the extracellular (EC) region and the 
chain toward the middle of the membrane. This structureexplains the selectivity of the DP receptor and the residues involved in the predicted binding site correlatevery well with available mutation experiments on DP, IP, TP, FP, and EP subtypes. We report moleculardynamics of DP in explicit lipid and water and find that the binding of the PGD2 agonist leads to correlatedrotations of helices of TM3 and TM7, whereas binding of antagonist leads to no such rotations. Thus,these motions may be related to the mechanism of activation.
chaintoward the extracellular (EC) region and the chain toward the middle of the membrane. This structureexplains the selectivity of the DP receptor and the residues involved in the predicted binding site correlatevery well with available mutation experiments on DP, IP, TP, FP, and EP subtypes. We report moleculardynamics of DP in explicit lipid and water and find that the binding of the PGD2 agonist leads to correlatedrotations of helices of TM3 and TM7, whereas binding of antagonist leads to no such rotations. Thus,these motions may be related to the mechanism of activation.