title: Understanding the regulation mechanisms of PAF receptor by agonists and antagonists: molecular modeling and molecular dynamics simulation studies.
abstract: Platelet-activating factor receptor (PAFR) is a member of G-protein coupled receptor (GPCR) superfamily. Understanding the regulation mechanisms of PAFR by its agonists and antagonists at the atomic level is essential for designing PAFR antagonists as drug candidates for treating PAF-mediated diseases. In this study, a 3D model of PAFR was constructed by a hierarchical approach integrating homology modeling, molecular docking and molecular dynamics (MD) simulations. Based on the 3D model, regulation mechanisms of PAFR by agonists and antagonists were investigated via three 8-ns MD simulations on the systems of apo-PAFR, PAFR-PAF and PAFR-GB. The simulations revealed that binding of PAF to PAFR triggers the straightening process of the kinked helix VI, leading to its activated state. In contrast, binding of GB to PAFR locks PAFR in its inactive state.
authors.affiliation: Drug Discovery and Design Centre, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
authors.forename: Chunshan
authors.initials: C
authors.lastname: Gui
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Oi W
authors.initials: OW
authors.lastname: Liew
authors.forename: Chum M
authors.initials: CM
authors.lastname: Puah
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D019295:Computational Biology; D003198:Computer Simulation; D046934:Ginkgolides / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007783:Lactones / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010972:Platelet Activating Factor / Q000737:chemistry*; D010980:Platelet Membrane Glycoproteins / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D046934:Ginkgolides; D007783:Lactones; D008051:Lipid Bilayers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D012243:Rhodopsin; C045856:ginkgolide B