title: Structure and localisation of drug binding sites on neurotransmitter transporters.
abstract: The dopamine (DAT), serotontin (SERT) and noradrenalin (NET) transporters are molecular targets for different classes of psychotropic drugs. The crystal structure of Aquifex aeolicus LeuT(Aa) was used as a template for molecular modeling of DAT, SERT and NET, and two putative drug binding sites (pocket 1 and 2) in each transporter were identified. Cocaine was docked into binding pocket 1 of DAT, corresponding to the leucine binding site in LeuT(Aa), which involved transmembrane helices (TMHs) 1, 3, 6 and 8. Clomipramine was docked into binding pocket 2 of DAT, involving TMHs 1, 3, 6, 10 and 11, and extracellular loops 4 and 6, corresponding to the clomipramine binding site in a crystal structure of a LeuT(Aa)-clomipramine complex. The structures of the proposed cocaine- and tricyclic antidepressant-binding sites may be of particular interest for the design of novel DAT interacting ligands.
authors.affiliation: Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Norway.
authors.forename: Aina W
authors.initials: AW
authors.lastname: Ravna
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.forename: Svein G
authors.initials: SG
authors.lastname: Dahl
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D050479:Neurotransmitter Transport Proteins / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011485:Protein Binding; D011619:Psychotropic Drugs / Q000493:pharmacokinetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D050479:Neurotransmitter Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011619:Psychotropic Drugs; D050486:Serotonin Plasma Membrane Transport Proteins