7LWD

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

Summary for 7LWD

• Entry DOI: 10.2210/pdb7lwd/pdb
• EMDB information: 23545
• Descriptor: Sodium-dependent serotonin transporter, heavy chain antibody fragment, light chain antibody fragment, ... (6 entities in total)
• Functional Keywords: antidepressant, complex, transporter, antibody, transport protein, transport protein-immune system complex, transport protein/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 86761.87

Authors

Yang, D.,Kalenderoglou, I.E.,Gouaux, E.,Coleman, J.A.,Loland, C.J. (deposition date: 2021-03-01, release date: 2021-08-11, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.65 Å)