7LWD

Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine and 15B8 Fab

7LWD の概要

• エントリーDOI: 10.2210/pdb7lwd/pdb
• EMDBエントリー: 23545
• 分子名称: Sodium-dependent serotonin transporter, heavy chain antibody fragment, light chain antibody fragment, ... (6 entities in total)
• 機能のキーワード: antidepressant, complex, transporter, antibody, transport protein, transport protein-immune system complex, transport protein/immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 86761.87

構造登録者

Yang, D.,Kalenderoglou, I.E.,Gouaux, E.,Coleman, J.A.,Loland, C.J. (登録日: 2021-03-01, 公開日: 2021-08-11, 最終更新日: 2024-10-23)

主引用文献

Plenge, P.,Yang, D.,Salomon, K.,Laursen, L.,Kalenderoglou, I.E.,Newman, A.H.,Gouaux, E.,Coleman, J.A.,Loland, C.J.
The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter.
Nat Commun, 12:5063-5063, 2021

PubMed Abstract: 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.

PubMed: 34417466
DOI: 10.1038/s41467-021-25363-3

実験手法

ELECTRON MICROSCOPY (3.65 Å)