2QJU

Crystal Structure of an NSS Homolog with Bound Antidepressant

Summary for 2QJU

• Entry DOI: 10.2210/pdb2qju/pdb
• Related: 2A65
• Descriptor: Transporter, octyl beta-D-glucopyranoside, SODIUM ION, ... (7 entities in total)
• Functional Keywords: neurotransmitter, transmembrane transport, integral membrane protein, antidepressant, nss, transport protein, structural genomics, psi-2, protein structure initiative, new york consortium on membrane protein structure, nycomps
• Biological source: Aquifex aeolicus
• Total number of polymer chains: 1
• Total formula weight: 58770.69

Authors

Zhou, Z.,Karpowich, N.K.,Wang, D.N.,New York Consortium on Membrane Protein Structure (NYCOMPS) (deposition date: 2007-07-09, release date: 2007-08-21, Last modification date: 2023-08-30)

Primary citation

Zhou, Z.,Zhen, J.,Karpowich, N.K.,Goetz, R.M.,Law, C.J.,Reith, M.E.,Wang, D.N.
LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake.
Science, 317:1390-1393, 2007

PubMed 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.

PubMed: 17690258
DOI: 10.1126/science.1147614

Experimental method

X-RAY DIFFRACTION (2.9 Å)