A common binding site for tricyclic and nontricyclic 5-hydroxytryptamine uptake inhibitors at the substrate recognition site of the neuronal sodium-dependent 5-hydroxytryptamine transporter

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

“…The central substrate binding pocket is an obvious candidate site for binding of competitive inhibitors, because inhibitor binding sites overlapping with the S1 substrate site offer a straightforward structural mechanism for competitive inhibition and are in agreement with pharmacological data showing that competitive inhibitors can be displaced in a concentration-dependent manner by substrates (Talvenheimo et al, 1979;Humphreys et al, 1988;Marcusson and Tiger, 1988;Graham et al, 1989;Apparsundaram et al, 2008). Although mutational studies on the SLC6 NTTs have identified residues in virtually all TM domains to be important for recognition of competitive inhibitors, the majority of the most sensitive residues reside within the regions that form the extracellular permeation pathway and the S1 substrate binding pocket (Barker et al, 1994(Barker et al, , 1998Barker and Blakely, 1996;Mortensen et al, 1999;Adkins et al, 2001;Larsen et al, 2004;Henry et al, 2006b;Beuming et al, 2008;Severinsen et al, 2008;Walline et al, 2008;Andersen et al, 2009bAndersen et al, , 2010Field et al, 2010).…”

Molecular Basis for Selective Serotonin Reuptake Inhibition by the Antidepressant Agent Fluoxetine (Prozac)

“…1) Wang et al, 2013). Combined with biochemical studies showing that most SSRIs inhibit SERT in a competitive manner (Graham et al, 1989;Koe et al, 1990;Apparsundaram et al, 2008), and several residues located within the S1 site of SERT and NET have been shown to be important for binding of SSRIs (Barker et al, 1999;Henry et al, 2006;Mason et al, 2007;Walline et al, 2008;Andersen et al, 2009Andersen et al, , 2010Koldsø et al, 2010;Sørensen et al, 2012), LeuBAT and Drosophila DAT seem to represent improved structural frameworks for studying the molecular pharmacology of human transporters compared with LeuT. Fluoxetine has been cocrystallized together with both LeuT and LeuBAT, and these studies have provided ambiguous insight into the binding mechanism of this important SSRI drug. Whereas fluoxetine binds to the S2 site in LeuT, it binds to the S1 site in LeuBAT ( Fig.…”

Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation

“…Together with the competitive binding mode of antidepressant drugs in SERT (23)(24)(25), this strongly suggests that the high affinity binding site for antidepressant drugs is overlapping with the S1 site in SERT. Recently, this notion was further supported by structures of the dopamine transporter (DAT) from Drosophila melanogaster and a LeuT/SERT hybrid protein co-crystallized with antidepressants (26,27).…”