LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake
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.
- Authors:
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL) National Synchrotron Light Source
- Sponsoring Org.:
- Doe - Office Of Science
- OSTI Identifier:
- 930532
- Report Number(s):
- BNL-80564-2008-JA
Journal ID: ISSN 0193-4511; SCEHDK; TRN: US200904%%772
- DOE Contract Number:
- DE-AC02-98CH10886
- Resource Type:
- Journal Article
- Resource Relation:
- Journal Name: Science; Journal Volume: 317
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 36 MATERIALS SCIENCE; ANTIDEPRESSANTS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DOPAMINE; LEUCINE; MUTAGENESIS; NORADRENALINE; SEROTONIN; SUBSTRATES; national synchrotron light source
Citation Formats
Zhou,Z., Zhen, J., Karpowich, N., Goetz, R., Law, C., Reith, M., and Wang, D.. LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake. United States: N. p., 2007.
Web. doi:10.1126/science.1147614.
Zhou,Z., Zhen, J., Karpowich, N., Goetz, R., Law, C., Reith, M., & Wang, D.. LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake. United States. doi:10.1126/science.1147614.
Zhou,Z., Zhen, J., Karpowich, N., Goetz, R., Law, C., Reith, M., and Wang, D.. Mon .
"LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake". United States.
doi:10.1126/science.1147614.
@article{osti_930532,
title = {LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake},
author = {Zhou,Z. and Zhen, J. and Karpowich, N. and Goetz, R. and Law, C. and Reith, M. and Wang, D.},
abstractNote = {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.},
doi = {10.1126/science.1147614},
journal = {Science},
number = ,
volume = 317,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
Find in Google Scholar
Search WorldCat to find libraries that may hold this journal