Steric hindrance mutagenesis in the conserved extracellular vestibule impedes allosteric binding of antidepressants to the serotonin transporter

Abstract

Background: The serotonin transporter contains an allosteric binding site with unknown location. Results: We use molecular modeling, mutagenesis, and zinc site engineering to locate and inhibit the allosteric binding site. Conclusion: Data are consistent with the allosteric binding site being located in the extracellular vestibule. Significance: This opens the search for a new generation of antidepressant drugs directed toward the proposed allosteric binding site.