National Institutes of Health/National Institute of Mental Health (NIH/NIMH)
5R37MH070039
米国
Howard Hughes Medical Institute (HHMI)
米国
Danish Council for Independent Research
7016-00272A
デンマーク
Lundbeckfonden
R344-2020-1020
デンマーク
Novo Nordisk Foundation
NNF19OC0058496
デンマーク
The Carlsberg Foundation
CF19-0527
デンマーク
The Carlsberg Foundation
CF20-0345
デンマーク
引用
ジャーナル: Nat Commun / 年: 2021 タイトル: The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. 著者: Per Plenge / Dongxue Yang / Kristine Salomon / Louise Laursen / Iris E Kalenderoglou / Amy H Newman / Eric Gouaux / Jonathan A Coleman / Claus J Loland / 要旨: Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin ...Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone.