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Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors

Author

Listed:
  • Ralph Gradisch

    (Medical University of Vienna, Institute of Physiology and Pharmacology)

  • Katharina Schlögl

    (TU Wien, Institute of Applied Synthetic Chemistry)

  • Erika Lazzarin

    (Medical University of Vienna, Institute of Physiology and Pharmacology)

  • Marco Niello

    (Medical University of Vienna, Institute of Physiology and Pharmacology
    Neuroscience area, Istituto Italiano di Tecnologia)

  • Julian Maier

    (Medical University of Vienna, Institute of Physiology and Pharmacology)

  • Felix P. Mayer

    (Florida Atlantic University, Department of Biomedical Science
    Stiles-Nicholson Brain Institute
    University of Copenhagen)

  • Leticia Alves da Silva

    (Medical University of Vienna, Institute of Physiology and Pharmacology)

  • Sophie M. C. Skopec

    (Medical University of Vienna, Institute of Physiology and Pharmacology)

  • Randy D. Blakely

    (Florida Atlantic University, Department of Biomedical Science
    Stiles-Nicholson Brain Institute)

  • Harald H. Sitte

    (Medical University of Vienna, Institute of Physiology and Pharmacology
    Al-Ahliyya Amman University, Hourani Center for Applied Scientific Research
    Medical University of Vienna, Center for Addiction Research and Science)

  • Marko D. Mihovilovic

    (TU Wien, Institute of Applied Synthetic Chemistry)

  • Thomas Stockner

    (Medical University of Vienna, Institute of Physiology and Pharmacology)

Abstract

The presynaptic serotonin transporter (SERT) clears extracellular serotonin following vesicular release to ensure temporal and spatial regulation of serotonergic signalling and neurotransmitter homeostasis. Prescription drugs used to treat neurobehavioral disorders, including depression, anxiety, and obsessive-compulsive disorder, trap SERT by blocking the transport cycle. In contrast, illicit drugs of abuse like amphetamines reverse SERT directionality, causing serotonin efflux. Both processes result in increased extracellular serotonin levels. By combining molecular dynamics simulations with biochemical experiments and using a homologous series of serotonin analogues, we uncovered the coupling mechanism between the substrate and the transporter, which triggers the uptake of serotonin. Free energy analysis showed that only scaffold-bound substrates could initiate SERT occlusion through attractive long-range electrostatic interactions acting on the bundle domain. The associated spatial requirements define substrate and inhibitor properties, enabling additional possibilities for rational drug design approaches.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44637-6
    DOI: 10.1038/s41467-023-44637-6
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    References listed on IDEAS

    as
    1. Kevin H. Wang & Aravind Penmatsa & Eric Gouaux, 2015. "Neurotransmitter and psychostimulant recognition by the dopamine transporter," Nature, Nature, vol. 521(7552), pages 322-327, May.
    2. 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.
    3. Jonathan A. Coleman & Dongxue Yang & Zhiyu Zhao & Po-Chao Wen & Craig Yoshioka & Emad Tajkhorshid & Eric Gouaux, 2019. "Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport," Nature, Nature, vol. 569(7754), pages 141-145, May.
    4. Per Plenge & Dongxue Yang & Kristine Salomon & Louise Laursen & Iris E. Kalenderoglou & Amy H. Newman & Eric Gouaux & Jonathan A. Coleman & Claus J. Loland, 2021. "The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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