title: X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine.
abstract: Most antidepressants elicit their therapeutic benefits through selective blockade of Na(+)/Cl(-)-coupled neurotransmitter transporters. Here we report X-ray structures of the Drosophila melanogaster dopamine transporter in complexes with the polycyclic antidepressants nisoxetine or reboxetine. The inhibitors stabilize the transporter in an outward-open conformation by occupying the substrate-binding site. These structures explain how interactions between the binding pocket and substituents on the aromatic rings of antidepressants modulate drug-transporter selectivity.
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland OR.
authors.forename: Aravind
authors.initials: A
authors.lastname: Penmatsa
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland OR.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Wang
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland OR.
authors.forename: Eric
authors.initials: E
authors.lastname: Gouaux
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry* / Q000378:metabolism*; D004331:Drosophila melanogaster; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D009025:Morpholines / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D000077593:Reboxetine
chemical_list: D000928:Antidepressive Agents; C493211:DAT protein, Drosophila; D050483:Dopamine Plasma Membrane Transport Proteins; D029721:Drosophila Proteins; D009025:Morpholines; D005473:Fluoxetine; C011386:nisoxetine; D000077593:Reboxetine