5I6X: X-ray Structure Of The Ts3 Human Serotonin Transporter Complexed With Paroxetine At The Central Site

Citation:
Abstract
The serotonin transporter (SERT) terminates serotonergic signalling through the sodium- and chloride-dependent reuptake of neurotransmitter into presynaptic neurons. SERT is a target for antidepressant and psychostimulant drugs, which block reuptake and prolong neurotransmitter signalling. Here we report X-ray crystallographic structures of human SERT at 3.15 A resolution bound to the antidepressants (S)-citalopram or paroxetine. Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8 and 10, directly blocking serotonin binding. We further identify the location of an allosteric site in the complex as residing at the periphery of the extracellular vestibule, interposed between extracellular loops 4 and 6 and transmembrane helices 1, 6, 10 and 11. Occupancy of the allosteric site sterically hinders ligand unbinding from the central site, providing an explanation for the action of (S)-citalopram as an allosteric ligand. These structures define the mechanism of antidepressant action in SERT, and provide blueprints for future drug design.
PDB ID: 5I6XDownload
MMDB ID: 138429
PDB Deposition Date: 2016/2/16
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 3.14  Å
Source Organism:
Mus musculus
Similar Structures:
Biological Unit for 5I6X: trimeric; determined by author and by software (PISA)
Molecular Components in 5I6X
Label Count Molecule
Proteins (3 molecules)
1
Sodium-dependent Serotonin Transporter(Gene symbol: SLC6A4)
Molecule annotation
1
8B6 Antibody, Heavy Chain
Molecule annotation
1
8B6 Antibody, Light Chain
Molecule annotation
Chemicals (7 molecules)
1
2
2
1
3
1
4
1
5
1
6
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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