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Antidepressant binding site in a bacterial homologue of neurotransmitter transporters

Author

Listed:
  • Satinder K. Singh

    (The Vollum Institute and,)

  • Atsuko Yamashita

    (Columbia University, 650 West 168th Street, New York, New York 10032, USA
    Present address: RIKEN SPring-8 Center, 1-1-1, Kouto, Sayo, Hyogo 679-5148, Japan.)

  • Eric Gouaux

    (The Vollum Institute and,
    Howard Hughes Medical Institute, Oregon Health and Science University, 3181 S.W. Sam Jackson Road, Portland, Oregon 97239, USA)

Abstract

Antidepressant design Tricyclic antidepressants act by inhibiting sodium-coupled neurotransmitter transporters in the brain, yet little is known about how these inhibitors work at the molecular level. The LeuT leucine transporter from the thermophilic bacterium Aquifex aeolicus is a homologue of the neurotransmitter transporters, and so far the only one that has proved amenable to structural analysis. Singh et al. therefore studied the mechanism of binding of three antidepressants — clomipramine, desipramine and imipramine — to LeuT. The drugs bind noncompetitively to an extracellular facing vestibule to inhibit substrate release. Although the norepinephrine and serotonin receptors in the human brain differ markedly from LeuT, this work has pinpointed an additional region that might be exploited for the development of new inhibitors with therapeutic potential.

Suggested Citation

  • Satinder K. Singh & Atsuko Yamashita & Eric Gouaux, 2007. "Antidepressant binding site in a bacterial homologue of neurotransmitter transporters," Nature, Nature, vol. 448(7156), pages 952-956, August.
    • Handle: RePEc:nat:nature:v:448:y:2007:i:7156:d:10.1038_nature06038
    DOI: 10.1038/nature06038
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    Cited by:

    1. Mariarosaria Ferraro & Matteo Masetti & Maurizio Recanatini & Andrea Cavalli & Giovanni Bottegoni, 2016. "Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics," PLOS ONE, Public Library of Science, vol. 11(12), pages 1-24, December.
    2. Eva Hellsberg & Gerhard F Ecker & Anna Stary-Weinzinger & Lucy R Forrest, 2019. "A structural model of the human serotonin transporter in an outward-occluded state," PLOS ONE, Public Library of Science, vol. 14(6), pages 1-25, June.
    3. Chunfeng Zhao & Sergei Yu Noskov, 2013. "The Molecular Mechanism of Ion-Dependent Gating in Secondary Transporters," PLOS Computational Biology, Public Library of Science, vol. 9(10), pages 1-12, October.
    4. Heidi Koldsø & Pernille Noer & Julie Grouleff & Henriette Elisabeth Autzen & Steffen Sinning & Birgit Schiøtt, 2011. "Unbiased Simulations Reveal the Inward-Facing Conformation of the Human Serotonin Transporter and Na+ Ion Release," PLOS Computational Biology, Public Library of Science, vol. 7(10), pages 1-14, October.
    5. Jufang Shan & Jonathan A Javitch & Lei Shi & Harel Weinstein, 2011. "The Substrate-Driven Transition to an Inward-Facing Conformation in the Functional Mechanism of the Dopamine Transporter," PLOS ONE, Public Library of Science, vol. 6(1), pages 1-15, January.
    6. Saher Afshan Shaikh & Emad Tajkhorshid, 2010. "Modeling and Dynamics of the Inward-Facing State of a Na+/Cl− Dependent Neurotransmitter Transporter Homologue," PLOS Computational Biology, Public Library of Science, vol. 6(8), pages 1-14, August.
    7. Michael V LeVine & Harel Weinstein, 2014. "NbIT - A New Information Theory-Based Analysis of Allosteric Mechanisms Reveals Residues that Underlie Function in the Leucine Transporter LeuT," PLOS Computational Biology, Public Library of Science, vol. 10(5), pages 1-15, May.

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