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The mechanism of a high-affinity allosteric inhibitor of the serotonin transporter

Author

Listed:
  • Per Plenge

    (University of Copenhagen)

  • Ara M. Abramyan

    (Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse—Intramural Research Program, National Institutes of Health)

  • Gunnar Sørensen

    (Lundbeck Research, H. Lundbeck A/S)

  • Arne Mørk

    (Lundbeck Research, H. Lundbeck A/S)

  • Pia Weikop

    (University of Copenhagen)

  • Ulrik Gether

    (University of Copenhagen)

  • Benny Bang-Andersen

    (Lundbeck Research, H. Lundbeck A/S
    University of Copenhagen)

  • Lei Shi

    (Computational Chemistry and Molecular Biophysics Unit, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse—Intramural Research Program, National Institutes of Health)

  • Claus J. Loland

    (University of Copenhagen)

Abstract

The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. SERT activity is modulated by antidepressants, e.g., S-citalopram and imipramine, to alleviate symptoms of depression and anxiety. SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In this study, our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 is allosterically coupled to the ligand binding to S2 through altering protein conformations. Remarkably, SERT inhibitor Lu AF60097, the first high-affinity S2-ligand reported and characterized here, allosterically couples the ligand binding to S1 through a similar mechanism. The SERT inhibition by Lu AF60097 is demonstrated by the potentiated imipramine binding and increased hippocampal serotonin level in rats. Together, we reveal a S1-S2 coupling mechanism that will facilitate rational design of high-affinity SERT allosteric inhibitors.

Suggested Citation

  • Per Plenge & Ara M. Abramyan & Gunnar Sørensen & Arne Mørk & Pia Weikop & Ulrik Gether & Benny Bang-Andersen & Lei Shi & Claus J. Loland, 2020. "The mechanism of a high-affinity allosteric inhibitor of the serotonin transporter," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15292-y
    DOI: 10.1038/s41467-020-15292-y
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    Cited by:

    1. Junyang Xu & Ziwei Hu & Lu Dai & Aditya Yadav & Yashan Jiang & Angelika Bröer & Michael G. Gardiner & Malcolm McLeod & Renhong Yan & Stefan Bröer, 2024. "Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19)," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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