Visualizing the binding mode of the antidepressant vilazodone on the serotonin transporter by cryo-EM

摘要: The serotonin transporter (SERT) belongs to the family of neurotransmitter sodium symporters (NSS) and is responsible for serotonin recycling and signal termination in the synaptic cleft of neurons. SERT is a therapeutical target for psychiatric disorders such as major depression. The standard medical treatment involves administration of selective serotonin reuptake inhibitors (SSRIs). All investigated SSRIs function as competitive inhibitors to serotonin. However, SERT also possesses an allosteric binding site and allosteric inhibitors may produce a novel therapeutic profile. Vilazodone is a novel SSRI. Its binding mode to SERT has not been fully explored. Recent work (Zhang et al. 2020) showed that the vilazodone binding site is located in the substrate binding (S1) site but protruding into the allosteric (S2) site. Here, we report that vilazodone is a non-competitive inhibitor of serotonin uptake and impedes …