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.
