Substrate binding and translocation of the serotonin transporter studied by docking and molecular dynamics simulations
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https://hdl.handle.net/10037/25226Date
2011-06-14Type
Journal articleTidsskriftartikkel
Peer reviewed
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
SpringerCitation
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):1073-1085Metadata
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Copyright 2011 The Author(s)