Substrate and inhibitor binding to the serotonin transporter: Insights from computational, crystallographic, and functional studies.
Neuropharmacology December 15, 2019 Talia Zeppelin, Lucy Kate Ladefoged, Steffen Sinning et al. 20 citations
The serotonin transporter (SERT) is a monoamine transporter that regulates serotonergic signaling by reuptaking serotonin from the synaptic cleft into the presynaptic neuron. Its dysregulation is linked to major depressive disorder (MDD), a leading cause of years lived with disease in 2016. Many antidepressants target SERT, and since the first bacterial SERT homologue structure was solved in 2005, crystallographic, computational, and functional studies have advanced understanding of drug binding. This review compares findings from these methods on substrate and inhibitor binding modes, highlighting caveats of each approach. It covers binding of the cognate substrate and various antidepressants—tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, multimodal drugs—and illicit drugs like cocaine, amphetamines, and ibogaine.