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

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 o

SUBMITTER: Sinning S 

PROVIDER: S-EPMC2832986 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature