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Yorodumi- PDB-7lwd: Cryo-EM structure of the wild-type human serotonin transporter co... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7lwd | ||||||||||||||||||||||||
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Title | Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine and 15B8 Fab | ||||||||||||||||||||||||
Components |
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Keywords | TRANSPORT PROTEIN/Immune System / antidepressant / complex / transporter / antibody / TRANSPORT PROTEIN / TRANSPORT PROTEIN-Immune System complex | ||||||||||||||||||||||||
Function / homology | Function and homology information negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / serotonergic synapse / Serotonin clearance from the synaptic cleft / positive regulation of serotonin secretion / cocaine binding / negative regulation of synaptic transmission, dopaminergic / sperm ejaculation / serotonin:sodium:chloride symporter activity / sodium ion binding ...negative regulation of cerebellar granule cell precursor proliferation / regulation of thalamus size / serotonergic synapse / Serotonin clearance from the synaptic cleft / positive regulation of serotonin secretion / cocaine binding / negative regulation of synaptic transmission, dopaminergic / sperm ejaculation / serotonin:sodium:chloride symporter activity / sodium ion binding / cellular response to cGMP / enteric nervous system development / negative regulation of organ growth / serotonin uptake / neurotransmitter transmembrane transporter activity / serotonin binding / monoamine transmembrane transporter activity / monoamine transport / conditioned place preference / vasoconstriction / brain morphogenesis / antiporter activity / neurotransmitter transport / syntaxin-1 binding / amino acid transport / nitric-oxide synthase binding / membrane depolarization / behavioral response to cocaine / social behavior / negative regulation of neuron differentiation / sodium ion transmembrane transport / endomembrane system / monoatomic cation channel activity / positive regulation of cell cycle / cellular response to retinoic acid / response to nutrient / platelet aggregation / memory / response to toxic substance / circadian rhythm / actin filament binding / integrin binding / response to estradiol / presynaptic membrane / postsynaptic membrane / response to hypoxia / endosome membrane / neuron projection / response to xenobiotic stimulus / membrane raft / focal adhesion / synapse / positive regulation of gene expression / identical protein binding / plasma membrane Similarity search - Function | ||||||||||||||||||||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | ||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.65 Å | ||||||||||||||||||||||||
Authors | Yang, D. / Kalenderoglou, I.E. / Gouaux, E. / Coleman, J.A. / Loland, C.J. | ||||||||||||||||||||||||
Funding support | United States, Denmark, 7items
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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. | ||||||||||||||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7lwd.cif.gz | 145.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7lwd.ent.gz | 116.6 KB | Display | PDB format |
PDBx/mmJSON format | 7lwd.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7lwd_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 7lwd_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 7lwd_validation.xml.gz | 45.4 KB | Display | |
Data in CIF | 7lwd_validation.cif.gz | 64 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/lw/7lwd ftp://data.pdbj.org/pub/pdb/validation_reports/lw/7lwd | HTTPS FTP |
-Related structure data
Related structure data | 23545MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Antibody , 2 types, 2 molecules HL
#2: Antibody | Mass: 12980.533 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Cell line: Hybridoma |
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#3: Antibody | 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 | 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 |
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#6: Sugar | ChemComp-NAG / |
-Non-polymers , 2 types, 2 molecules
#4: Chemical | ChemComp-IXX / |
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#5: Chemical | ChemComp-YG7 / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Molecular weight | Value: 0.105 MDa / Experimental value: NO | ||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) | Organism: Homo sapiens (human) | ||||||||||||||||||||||||
Buffer solution | pH: 8 | ||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: monodisperse | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 43 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.15.2_3472: / Classification: refinement | ||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING ONLY | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 415288 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: RIGID BODY FIT | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 6AWN | ||||||||||||||||||||||||
Refine LS restraints |
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