National Institutes of Health/National Institute of Mental Health (NIH/NIMH)
5R37MH070039
United States
Howard Hughes Medical Institute (HHMI)
United States
Danish Council for Independent Research
7016-00272A
Denmark
Lundbeckfonden
R344-2020-1020
Denmark
Novo Nordisk Foundation
NNF19OC0058496
Denmark
The Carlsberg Foundation
CF19-0527
Denmark
The Carlsberg Foundation
CF20-0345
Denmark
Citation
Journal: Nat Commun / Year: 2021 Title: The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. Authors: Per Plenge / Dongxue Yang / Kristine Salomon / Louise Laursen / Iris E Kalenderoglou / Amy H Newman / Eric Gouaux / Jonathan A Coleman / Claus J Loland / 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 ...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.
Mass: 12980.533 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Cell line: Hybridoma
#3: Antibody
lightchainantibodyfragment
Mass: 11776.065 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Cell line: Hybridoma
-
Protein / Sugars , 2 types, 2 molecules A
#1: Protein
Sodium-dependentserotonintransporter / SERT / 5HT transporter / 5HTT / Solute carrier family 6 member 4
Mass: 61062.129 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A4, HTT, SERT / Cell line (production host): Hek293 GnTi- / Production host: Homo sapiens (human) / References: UniProt: P31645
In the structure databanks used in Yorodumi, some data are registered as the other names, "COVID-19 virus" and "2019-nCoV". Here are the details of the virus and the list of structure data.
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)
EMDB accession codes are about to change! (news from PDBe EMDB page)
The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
The EM Navigator/Yorodumi systems omit the EMD- prefix.
Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator
Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.
Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi