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Substrate binding and translocation of the serotonin transporter studied by docking and molecular dynamics simulations

Permanent link
https://hdl.handle.net/10037/25226
DOI
https://doi.org/10.1007/s00894-011-1133-1
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Date
2011-06-14
Type
Journal article
Tidsskriftartikkel
Peer reviewed

Author
Gabrielsen, Mari; Ravna, aina westrheim; Kristiansen, kurt; Sylte, Ingebrigt
Abstract
The serotonin (5-HT) transporter (SERT) plays an important role in the termination of 5-HT-mediated neurotransmission by transporting 5-HT away from the synaptic cleft and into the presynaptic neuron. In addition, SERT is the main target for antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs). The three-dimensional (3D) structure of SERT has not yet been determined, and little is known about the molecular mechanisms of substrate binding and transport, though such information is very important for the development of new antidepressant drugs. In this study, a homology model of SERT was constructed based on the 3D structure of a prokaryotic homologous leucine transporter (LeuT) (PDB id: 2A65). Eleven tryptamine derivates (including 5-HT) and the SSRI (S)-citalopram were docked into the putative substrate binding site, and two possible binding modes of the ligands were found. To study the conformational effect that ligand binding may have on SERT, two SERT–5-HT and two SERT–(S)-citalopram complexes, as well as the SERT apo structure, were embedded in POPC lipid bilayers and comparative molecular dynamics (MD) simulations were performed. Our results show that 5-HT in the SERT– 5-HTB complex induced larger conformational changes in the cytoplasmic parts of the transmembrane helices of SERT than any of the other ligands. Based on these results, we suggest that the formation and breakage of ionic interactions with amino acids in transmembrane helices 6 and 8 and intracellular loop 1 may be of importance for substrate translocation.
Publisher
Springer
Citation
Gabrielsen M, Ravna aw, Kristiansen k, Sylte IS. Substrate binding and translocation of the serotonin transporter studied by docking and molecular dynamics simulations. Journal of Molecular Modeling. 2012;18(3):1073-1085
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