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

PLoS One. 2019 Jun 28;14(6):e0217377. doi: 10.1371/journal.pone.0217377. eCollection 2019.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antidepressive Agents / chemistry*
  • Binding Sites
  • Humans
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Serotonin Plasma Membrane Transport Proteins / chemistry*
  • Serotonin Plasma Membrane Transport Proteins / metabolism


  • Antidepressive Agents
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins

Grant support

This work was funded by the Austrian Science Fund, grant W1232, https://www.fwf.ac.at/en/ (to EH), and by the Division of Intramural Research of the NIH, National Institute of Neurological Disorders and Stroke, https://www.ninds.nih.gov/ (to LRF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.