Structural basis of vilazodone dual binding mode to the serotonin transporter.

ABSTRACT: The serotonin transporter (SERT) plays a pivotal role in regulating serotonin (5-HT) signaling and is a key target in the treatment of psychiatric disorders. SERT has a binding site (S1) for 5-HT that also serves as a high-affinity binding site for antidepressants. The antidepressant vilazodone has been shown to inhibit SERT by binding to an allosteric site. Here, we present the cryo-EM structure of SERT with vilazodone bound to the S1 site and extending towards the allosteric site. We systematically dissect the vilazodone molecule into fragments and find that the terminal indole ring is the key determinant of its high affinity to SERT. Further, unlike typical Na⁺-dependent SERT-selective antidepressants, vilazodone exhibits a dissociation constant (K_D) for purified S

SUBMITTER: Kalenderoglou IE 

PROVIDER: S-EPMC12627810 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature