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The serotonin transporter (SERT) is the primary target for the selective serotonin reuptake inhibitors (SSRIs). However, the structural basis for the extraordinarily high binding affinity of the widely prescribed SSRI, paroxetine, to human SERT (hSERT) has not yet been fully elucidated. Our previous findings unveiled a plausible ambiguity in paroxetine's binding orientations that may constitute an integral component of this SSRI's high affinity for hSERT. Herein, we investigate factors contributing to paroxetine's high affinity by modifying both the ligand and the protein. We generated a series of bromine (Br)-containing derivatives and found that the one in which the 4-F of paroxetine had been replaced with the chemically similar but more electron-rich Br atom (13) had the highest affinity. By comparatively characterizing the binding of paroxetine and 13 to both wild type (WT) and a construct harboring a paroxetine-sensitive mutation in the binding cavity, we identified a mechanistic determinant responsible for the pose ambiguity of paroxetine, which can guide future drug design.

Background: Bacterial homologues of neurotransporters served as structural paradigms for interpretation of the functional data available for their eukaryotic counterparts. Results: We identified and characterized a close bacterial homologue of the rat vesicular monoamine transporter rVMAT2. Conclusion: BbMAT is a multidrug antiporter. Conserved membrane-embedded carboxyls play a role in substrate and proton transport. Significance: Understanding of the bacterial homologue should provide insights into rVMAT2.

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