title: Prediction of the 3D structure and dynamics of human DP G-protein coupled receptor bound to an agonist and an antagonist.
abstract: Prostanoids play important physiological roles in the cardiovascular and immune systems and in 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 antagonists has been hampered by the lack of 3D structures for these receptors. We report here the 3D structure for the 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 the endogenous agonist (PGD2) to DP. Based on our structure, we predicted the binding of different antagonists and optimized them. We find that PGD2 binds vertically to DP in the TM1237 region with the alpha chain toward the extracellular (EC) region and the omega chain toward the middle of the membrane. This structure explains the selectivity of the DP receptor and the residues involved in the predicted binding site correlate very well with available mutation experiments on DP, IP, TP, FP, and EP subtypes. We report molecular dynamics of DP in explicit lipid and water and find that the binding of the PGD2 agonist leads to correlated rotations 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.
authors: Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, California 91125, USA.
authors: Youyong
authors: Y
authors: Li
authors: Fangqiang
authors: F
authors: Zhu
authors: Nagarajan
authors: N
authors: Vaidehi
authors: William A
authors: WA
authors: Goddard
authors: Felix
authors: F
authors: Sheinerman
authors: Stephan
authors: S
authors: Reiling
authors: Isabelle
authors: I
authors: Morize
authors: Lan
authors: L
authors: Mu
authors: Keith
authors: K
authors: Harris
authors: Ali
authors: A
authors: Ardati
authors: Abdelazize
authors: A
authors: Laoui
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015230:Prostaglandin D2 / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D008055:Lipids; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D014867:Water; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor
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