Novel computational model for the interaction of dopamine with the D2 receptor. 1993

H Moereels, and J E Leysen
Department of Theoretical Medicinal Chemistry, Janssen Research Foundation, Beerse, Belgium.

With the use of molecular modelling and computational chemistry, two models were obtained showing the binding of dopamine to part of the D2 receptor. These models consist of a molecular complex containing dopamine, the transmembrane domains (TM) 3, 4 and 5, a small part of the extracellular loop just before TM3 and a larger part of the loop connecting TM4 and TM5. The models are further characterized by the presence of two disulphide bonds: one between TM3 and TM4 and a second linking the Cys residue before TM3 with the Cys residue in the loop between TM4 and TM5. In the first model, the beta-adrenergic receptor is used as a reference with the catechol moieties of dopamine interacting with two Ser residues in TM5, and the Asp residue in TM3 interacting with the protonated nitrogen of dopamine. In the second model, dopamine is positioned between the TM without interaction assumptions. In both models the TM positions are close to the arrangement of the alpha-helix ordering as found in bacteriorhodopsin. Energy minimization was accomplished using these two starting structures. The two minimized complexes show different molecular interactions that make good chemical sense and are in agreement with reported X-ray data of different proteins. The disulphide bond between TM3 and 4 is apparently unique to the D2 and D3 receptors. The first minimized complex revealed that not Ser194, as in the beta-receptor, but Ser 193 interacted with the meta-hydroxyl of dopamine, although a proper hydrogen bond with Ser194 was initially present in the starting structure. The para-hydroxyl group interacted with Ser197.(ABSTRACT TRUNCATED AT 250 WORDS)

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D004220 Disulfides Chemical groups containing the covalent disulfide bonds -S-S-. The sulfur atoms can be bound to inorganic or organic moieties. Disulfide
D004298 Dopamine One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action. Hydroxytyramine,3,4-Dihydroxyphenethylamine,4-(2-Aminoethyl)-1,2-benzenediol,Dopamine Hydrochloride,Intropin,3,4 Dihydroxyphenethylamine,Hydrochloride, Dopamine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D006860 Hydrogen Bonding A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. Hydrogen Bonds,Bond, Hydrogen,Hydrogen Bond
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013816 Thermodynamics A rigorously mathematical analysis of energy relationships (heat, work, temperature, and equilibrium). It describes systems whose states are determined by thermal parameters, such as temperature, in addition to mechanical and electromagnetic parameters. (From Hawley's Condensed Chemical Dictionary, 12th ed) Thermodynamic

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