LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.

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Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN

LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.

Science. 2007 Sep 7;317(5843):1390-3. Epub 2007 Aug 9.

PubMed ID

17690258 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Transporter	O67854	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Desipramine	Sodium-dependent serotonin transporter	IC 50 (nM)	108	N/A	N/A	Details