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Submitted on July 10, 2007
Accepted on July 30, 2007
LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake
Zheng Zhou 1, Juan Zhen 2, Nathan K. Karpowich 1, Regina M. Goetz 1, Christopher J. Law 1, Maarten E. A. Reith 2*, Da-Neng Wang 1*
1 Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA. 2 Departments of Psychiatry and Pharmacology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
* To whom correspondence should be addressed.
Maarten E. A. Reith , E-mail: maarten.reith{at}med.nyu.edu Da-Neng Wang , E-mail: wang{at}saturn.med.nyu.edu
Tricyclic antidepressants exert their pharmacological effect—inhibitingthe reuptake of serotonin, norepinephrine, and dopamine—bydirectly blocking neurotransmitter transporters (SERT, NET,and DAT, respectively) in the presynaptic membrane. The drug-bindingsite and the mechanism of this inhibition are poorly understood.We determined the crystal structure at 2.9 Å of the bacterialleucine 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 cavityof the transporter and is held in place by a hairpin loop andby a salt bridge. This binding site is separated from the leucine-bindingsite by the extracellular gate of the transporter. By directlylocking the gate, desipramine prevents conformational changesand blocks substrate transport. Mutagenesis experiments on humanSERT and DAT indicate that both the desipramine-binding siteand its inhibition mechanism are probably conserved in the humanneurotransmitter transporters.
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