X-ray structures and mechanism of the human serotonin transporter

Coleman, Jonathan A.; Green, Evan M.; Gouaux, Eric

doi:10.1038/nature17629

Title: X-ray structures and mechanism of the human serotonin transporter

Journal Article · Wed Apr 06 00:00:00 EDT 2016 · Nature (London)

DOI:https://doi.org/10.1038/nature17629· OSTI ID:1249242

Coleman, Jonathan A. ^[1]; Green, Evan M. ^[2]; Gouaux, Eric ^[1]

Oregon Health & Science Univ. Portland, OR (United States)
Univ. of California, San Francisco, CA (United States); Oregon Health & Science Univ., Portland, OR (United States)

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. Furthermore, these structures define the mechanism of antidepressant action in SERT, and provide blueprints for future drug design.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: 5R37MH070039

OSTI ID:: 1249242

Journal Information:: Nature (London), Vol. 532, Issue 7599; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 403 works

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