Binding and orientation of tricyclic antidepressants within the central substrate site of the human serotonin transporter.

The Journal of Biological Chemistry
Steffen SinningOve Wiborg

Abstract

Tricyclic antidepressants (TCAs) have been used for decades, but their orientation within and molecular interactions with their primary target is yet unsettled. The recent finding of a TCA binding site in the extracellular vestibule of the bacterial leucine transporter 11 A above the central site has prompted debate about whether this vestibular site in the bacterial transporter is applicable to binding of antidepressants to their relevant physiological target, the human serotonin transporter (hSERT). We present an experimentally validated structural model of imipramine and analogous TCAs in the central substrate binding site of hSERT. Two possible binding modes were observed from induced fit docking calculations. We experimentally validated a single binding mode by combining mutagenesis of hSERT with uptake inhibition studies of different TCA analogs according to the paired mutation ligand analog complementation paradigm. Using this experimental method, we identify a salt bridge between the tertiary aliphatic amine and Asp(98). Furthermore, the 7-position of the imipramine ring is found vicinal to Phe(335), and the pocket lined by Ala(173) and Thr(439) is utilized by 3-substituents. These protein-ligand contact points unambigu...Continue Reading

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Citations

Oct 2, 2013·Naunyn-Schmiedeberg's Archives of Pharmacology·Timothy LynaghLesley J Bryan-Lluka
Sep 29, 2012·ACS Chemical Neuroscience·Kasper SeverinsenSteffen Sinning
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