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A structural model of the human serotonin transporter in an outward-occluded state

Author

Listed:
  • Eva Hellsberg
  • Gerhard F Ecker
  • Anna Stary-Weinzinger
  • Lucy R Forrest

Abstract

The human serotonin transporter hSERT facilitates the reuptake of its endogenous substrate serotonin from the synaptic cleft into presynaptic neurons after signaling. Reuptake regulates the availability of this neurotransmitter and therefore hSERT plays an important role in balancing human mood conditions. In 2016, the first 3D structures of this membrane transporter were reported in an inhibitor-bound, outward-open conformation. These structures revealed valuable information about interactions of hSERT with antidepressant drugs. Nevertheless, the question remains how serotonin facilitates the specific conformational changes that open and close pathways from the synapse and to the cytoplasm as required for transport. Here, we present a serotonin-bound homology model of hSERT in an outward-occluded state, a key intermediate in the physiological cycle, in which the interactions with the substrate are likely to be optimal. Our approach uses two template structures and includes careful refinement and comprehensive computational validation. According to microsecond-long molecular dynamics simulations, this model exhibits interactions between the gating residues in the extracellular pathway, and these interactions differ from those in an outward-open conformation of hSERT bound to serotonin. Moreover, we predict several features of this state by monitoring the intracellular gating residues, the extent of hydration, and, most importantly, protein-ligand interactions in the central binding site. The results illustrate common and distinct characteristics of these two transporter states and provide a starting point for future investigations of the transport mechanism in hSERT.

Suggested Citation

  • 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.
  • Handle: RePEc:plo:pone00:0217377
    DOI: 10.1371/journal.pone.0217377
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    References listed on IDEAS

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    1. 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.
    2. Ingvar R. Möller & Marika Slivacka & Anne Kathrine Nielsen & Søren G. F. Rasmussen & Ulrik Gether & Claus J. Loland & Kasper D. Rand, 2019. "Conformational dynamics of the human serotonin transporter during substrate and drug binding," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    3. 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.
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