title: Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques.
abstract: We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model.
authors.affiliation: Department of Biophysics, School of Medicine, Bahcesehir University , 34349 Istanbul, Turkey.
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.affiliation: Department of Biophysics, School of Medicine, Bahcesehir University , 34349 Istanbul, Turkey.|Department of Chemistry, Istanbul Technical University , 34469 Istanbul, Turkey.
authors.forename: Ramin Ekhteiari
authors.initials: RE
authors.lastname: Salmas
authors.affiliation: Molecular Simulations and Design Group, Max-Planck Institute for Dynamics of Complex Technical Systems , Sandtorstrasse 1, 39106, Magdeburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Stein
authors.affiliation: Department of Chemistry, Istanbul Technical University , 34469 Istanbul, Turkey.
authors.forename: Mine
authors.initials: M
authors.lastname: Yurtsever
authors.affiliation: Departments of Pharmacology and Psychiatry, University of Toronto , 260 Heath Street West, Unit 605, M5P 3L6, Toronto, Ontario Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
mesh_terms: D001058:Apomorphine / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation / Q000379:methods*; D011485:Protein Binding / Q000187:drug effects; D015202:Protein Engineering; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D001058:Apomorphine; D004298:Dopamine
keywords: D2High and D2Low states of dopamine; Dopamine D2 receptor; GPCR dimerization; molecular docking; protein engineering