Abstract
Tricyclic antidepressants exert their pharmacological effect-inhibiting the reuptake of serotonin, norepinephrine, and dopamine-by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This binding site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.
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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Amino Acid Sequence
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Animals
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Antidepressive Agents, Tricyclic / chemistry
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Antidepressive Agents, Tricyclic / metabolism*
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism*
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Binding Sites
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Caenorhabditis elegans Proteins / chemistry
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Caenorhabditis elegans Proteins / metabolism
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Cell Line
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Conserved Sequence
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Crystallography, X-Ray
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Desipramine / chemistry
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Desipramine / metabolism*
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Dopamine / chemistry
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Dopamine / metabolism
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Dopamine Uptake Inhibitors / chemistry
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Dopamine Uptake Inhibitors / metabolism
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Drosophila Proteins / chemistry
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Drosophila Proteins / metabolism
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Humans
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Leucine / chemistry
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Leucine / metabolism
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Models, Molecular
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Molecular Sequence Data
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Neurotransmitter Uptake Inhibitors / chemistry
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Neurotransmitter Uptake Inhibitors / metabolism*
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Norepinephrine / chemistry
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Norepinephrine / metabolism
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Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors
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Norepinephrine Plasma Membrane Transport Proteins / chemistry
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Norepinephrine Plasma Membrane Transport Proteins / metabolism
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Plasma Membrane Neurotransmitter Transport Proteins / chemistry
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Plasma Membrane Neurotransmitter Transport Proteins / metabolism*
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Protein Binding
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Protein Conformation
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Selective Serotonin Reuptake Inhibitors / chemistry
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Selective Serotonin Reuptake Inhibitors / metabolism
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Sequence Homology, Amino Acid
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Serotonin / chemistry
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Serotonin / metabolism
Substances
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Antidepressive Agents, Tricyclic
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Bacterial Proteins
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Caenorhabditis elegans Proteins
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Dopamine Uptake Inhibitors
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Drosophila Proteins
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Neurotransmitter Uptake Inhibitors
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Norepinephrine Plasma Membrane Transport Proteins
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Plasma Membrane Neurotransmitter Transport Proteins
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Serotonin Uptake Inhibitors
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Serotonin
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Leucine
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Desipramine
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Dopamine
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Norepinephrine