Abstract
The serotonin transporter (SERT) is an integral membrane protein that exploits preexisting sodium-, chloride-, and potassium ion gradients to catalyze the thermodynamically unfavorable movement of synaptic serotonin into the presynaptic neuron. SERT has garnered significant clinical attention partly because it is the target of multiple psychoactive agents, including the antidepressant paroxetine (Paxil), the most potent selective serotonin reuptake inhibitor known. However, the binding site and orientation of paroxetine in SERT remain controversial. To provide molecular insight, we constructed SERT homology models based on the Drosophila melanogaster dopamine transporter and docked paroxetine to these models. We tested the predicted binding configurations with a combination of radioligand binding and flux assays on wild-type and mutant SERTs. Our data suggest that the orientation of paroxetine, specifically its fluorophenyl ring, in SERT’s substrate binding site directly depends on this pocket’s charge distribution, and thereby provide an avenue toward understanding and enhancing high-affinity antidepressant activity.
Highlights
To narrow down the residues responsible for paroxetine recognition, we began by searching for serotonin transporter (SERT) homologues with divergent potencies for paroxetine compared with hsSERT and chose the ones from Drosophila melanogaster and chicken (Gallus gallus, ggSERT) (Fig. 3)
Paroxetine is the most potent SERT inhibitor and one of the most effective therapeutics currently available for a broad spectrum of neuropsychiatric illnesses, yet its precise molecular interactions within its binding site have remained elusive. Part of this dearth of knowledge stems from the paucity of studies expressly targeted toward paroxetine, unlike the prototypical antidepressants escitalopram[13,15,55,56] or imipramine[12,55], but much of the deficiency is due to the unfortunate outcome of not having identified an amino acid which, when mutated, influences the affinity of paroxetine as much as it does that of other antidepressants
One conceivable exception is a report that characterized a series of cross-species chimeras between ggSERT and hsSERT followed by selected site-directed mutants and conjectured that positions 169 as well as 172 in hsSERT play important roles in “sensing the N-methylation state of SERT antagonists”[42]
Summary
Use of an induced fit receptor structure in virtual screening. Novel procedure for modeling ligand/receptor induced fit effects. A. et al Glide: a new approach for rapid, accurate docking and scoring
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