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X-ray structures and mechanism of the human serotonin transporter

Author

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  • Jonathan A. Coleman

    (Vollum Institute, Oregon Health & Science University)

  • Evan M. Green

    (Vollum Institute, Oregon Health & Science University
    Present address: Graduate Group in Biophysics, University of California, San Francisco, San Francisco, California 94158, USA.)

  • Eric Gouaux

    (Vollum Institute, Oregon Health & Science University
    Howard Hughes Medical Institute, Oregon Health & Science University)

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.

Suggested Citation

  • Jonathan A. Coleman & Evan M. Green & Eric Gouaux, 2016. "X-ray structures and mechanism of the human serotonin transporter," Nature, Nature, vol. 532(7599), pages 334-339, April.
    • Handle: RePEc:nat:nature:v:532:y:2016:i:7599:d:10.1038_nature17629
    DOI: 10.1038/nature17629
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    Cited by:

    1. Huanyu Z. Li & Ashley C. W. Pike & Irina Lotsaris & Gamma Chi & Jesper S. Hansen & Sarah C. Lee & Karin E. J. Rödström & Simon R. Bushell & David Speedman & Adam Evans & Dong Wang & Didi He & Leela Sh, 2024. "Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Ralph Gradisch & Katharina Schlögl & Erika Lazzarin & Marco Niello & Julian Maier & Felix P. Mayer & Leticia Alves da Silva & Sophie M. C. Skopec & Randy D. Blakely & Harald H. Sitte & Marko D. Mihovi, 2024. "Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Talia Zeppelin & Lucy Kate Ladefoged & Steffen Sinning & Xavier Periole & Birgit Schiøtt, 2018. "A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition," PLOS Computational Biology, Public Library of Science, vol. 14(1), pages 1-24, January.

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