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Article

Prediction of the 3D Structure and Dynamics of Human DP G-Protein Coupled Receptor Bound to an Agonist and an Antagonist

Supporting Info

Youyong Li,^† Fangqiang Zhu,^† Nagarajan Vaidehi,*^†^‡ William A. Goddard, III,*^† Felix Sheinerman,^§ Stephan Reiling,^§ Isabelle Morize,^§ Lan Mu,^§ Keith Harris,^§ Ali Ardati,^§ and Abdelazize Laoui^§;

Contribution from the Materials and Process Simulation Center (MC 139-74), California Institute of Technology, Pasadena, California 91125, and Sanofi-Aventis Pharma, Bridgewater, New Jersey 08807-0800

J. Am. Chem. Soc., 2007, 129 (35), pp 10720–10731

DOI: 10.1021/ja070865d

Publication Date (Web): August 11, 2007

†

California Institute of Technology.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

‡

Present address: Division of Immunology, Beckman Research Institute of City of Hope, 1500, Duarte Road, Duarte, CA 91010.

Sanofi-Aventis Pharma.

, wag@wag.caltech.edu, ; , NVaidehi@coh.org

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 α chain toward the extracellular (EC) region and the ω 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.

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