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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.

SUBMITTER: Penmatsa A

PROVIDER: S-EPMC4608549 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine.

Penmatsa Aravind A Wang Kevin H KH Gouaux Eric E

Nature structural & molecular biology 20150511 6

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 th ...[more]

PMID: 25961798

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