title: Modelling the interaction of catecholamines with the alpha 1A adrenoceptor towards a ligand-induced receptor structure.
abstract: Adrenoceptors are members of the important G protein coupled receptor family for which the detailed mechanism of activation remains unclear. In this study, we have combined docking and molecular dynamics simulations to model the ligand induced effect on an homology derived human alpha1A adrenoceptor. Analysis of agonist/alpha1A adrenoceptor complex interactions focused on the role of the charged amine group, the aromatic ring, the N-methyl group of adrenaline, the beta hydroxyl group and the catechol meta and para hydroxyl groups of the catecholamines. The most critical interactions for the binding of the agonists are consistent with many earlier reports and our study suggests new residues possibly involved in the agonist-binding site, namely Thr-174 and Cys-176. We further observe a number of structural changes that occur upon agonist binding including a movement of TM-V away from TM-III and a change in the interactions of Asp-123 of the conserved DRY motif. This may cause Arg-124 to move out of the TM helical bundle and change the orientation of residues in IC-II and IC-III, allowing for increased affinity of coupling to the G-protein.
authors.affiliation: Department of Chemistry, Trinity College, University of Dublin, Dublin 2, Ireland.
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Kinsella
authors.forename: Isabel
authors.initials: I
authors.lastname: Rozas
authors.forename: Graeme W
authors.initials: GW
authors.lastname: Watson
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists; D020816:Amino Acid Motifs; D002395:Catecholamines / Q000378:metabolism*; D019295:Computational Biology; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism*; D040681:Structural Homology, Protein
chemical_list: C547713:ADRA1A protein, human; D058646:Adrenergic alpha-1 Receptor Agonists; D002395:Catecholamines; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1