Structure and localisation of drug binding sites on neurotransmitter transporters.
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.
Ravna
Aina W
AW
Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Norway.
Sylte
Ingebrigt
I
Dahl
Svein G
SG
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
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