5I71

X-ray structure of the ts3 human serotonin transporter complexed with s-citalopram at the central site

Summary for 5I71

• Entry DOI: 10.2210/pdb5i71/pdb
• Related: 5I66 5I6X 5I6Z 5I73 5I74 5I75
• Descriptor: Sodium-dependent serotonin transporter, 8B6 antibody, heavy chain, 8B6 antibody, light chain, ... (10 entities in total)
• Functional Keywords: membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 110552.30

Authors

Coleman, J.A.,Green, E.M.,Gouaux, E. (deposition date: 2016-02-16, release date: 2016-04-13, Last modification date: 2020-07-29)

Primary citation

Coleman, J.A.,Green, E.M.,Gouaux, E.
X-ray structures and mechanism of the human serotonin transporter.
Nature, 532:334-339, 2016

PubMed 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 Å 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.

PubMed: 27049939
DOI: 10.1038/nature17629

Experimental method

X-RAY DIFFRACTION (3.15 Å)