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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antidepressive Agents / chemistry
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Antidepressive Agents / metabolism
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Crystallography, X-Ray
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Dopamine Plasma Membrane Transport Proteins / chemistry*
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Dopamine Plasma Membrane Transport Proteins / metabolism*
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Drosophila Proteins / chemistry*
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Drosophila Proteins / metabolism*
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Drosophila melanogaster
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Fluoxetine / analogs & derivatives*
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Fluoxetine / chemistry
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Fluoxetine / metabolism
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Morpholines / chemistry*
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Morpholines / metabolism*
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Protein Binding
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Reboxetine
Substances
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Antidepressive Agents
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DAT protein, Drosophila
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Dopamine Plasma Membrane Transport Proteins
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Drosophila Proteins
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Morpholines
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Fluoxetine
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nisoxetine
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Reboxetine