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Yorodumi- EMDB-23545: Cryo-EM structure of the wild-type human serotonin transporter co... -
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-Basic information
Entry | Database: EMDB / ID: EMD-23545 | ||||||||||||||||||||||||
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Title | Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine and 15B8 Fab | ||||||||||||||||||||||||
Map data | Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine and 15B8 Fab | ||||||||||||||||||||||||
Sample |
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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 | single particle reconstruction / cryo EM / Resolution: 3.65 Å | ||||||||||||||||||||||||
Authors | Yang D / Kalenderoglou IE / Gouaux E / Coleman JA / Loland CJ | ||||||||||||||||||||||||
Funding support | United States, Denmark, 7 items
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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 | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_23545.map.gz | 230 MB | EMDB map data format | |
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Header (meta data) | emd-23545-v30.xml emd-23545.xml | 23.8 KB 23.8 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_23545_fsc.xml | 15.2 KB | Display | FSC data file |
Images | emd_23545.png | 85.4 KB | ||
Masks | emd_23545_msk_1.map | 244.1 MB | Mask map | |
Others | emd_23545_additional_1.map.gz emd_23545_half_map_1.map.gz emd_23545_half_map_2.map.gz | 119.1 MB 226.5 MB 226.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23545 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23545 | HTTPS FTP |
-Validation report
Summary document | emd_23545_validation.pdf.gz | 716.1 KB | Display | EMDB validaton report |
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Full document | emd_23545_full_validation.pdf.gz | 715.6 KB | Display | |
Data in XML | emd_23545_validation.xml.gz | 22.1 KB | Display | |
Data in CIF | emd_23545_validation.cif.gz | 28.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23545 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23545 | HTTPS FTP |
-Related structure data
Related structure data | 7lwdMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_23545.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine and 15B8 Fab | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.648 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_23545_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: unsharpened map
File | emd_23545_additional_1.map | ||||||||||||
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Annotation | unsharpened map | ||||||||||||
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Density Histograms |
-Half map: halfmap1
File | emd_23545_half_map_1.map | ||||||||||||
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Annotation | halfmap1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: halfmap2
File | emd_23545_half_map_2.map | ||||||||||||
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Annotation | halfmap2 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : serotonin transporter 8B6 Fab complex
Entire | Name: serotonin transporter 8B6 Fab complex |
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Components |
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-Supramolecule #1: serotonin transporter 8B6 Fab complex
Supramolecule | Name: serotonin transporter 8B6 Fab complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Molecular weight | Theoretical: 105 KDa |
-Supramolecule #2: serotonin transporter
Supramolecule | Name: serotonin transporter / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Homo sapiens (human) |
-Supramolecule #3: 8B6 antibody
Supramolecule | Name: 8B6 antibody / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3 |
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Source (natural) | Organism: Mus musculus (house mouse) |
-Macromolecule #1: Sodium-dependent serotonin transporter
Macromolecule | Name: Sodium-dependent serotonin transporter / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 61.062129 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: GERETWGKKV DFLLSVIGYA VDLGNVWRFP YICYQNGGGA FLLPYTIMAI FGGIPLFYME LALGQYHRNG CISIWRKICP IFKGIGYAI CIIAFYIASY YNTIMAWALY YLISSFTDQL PWTSCKNSWN TGNCTNYFSE DNITWTLHST SPAEEFYTRH V LQIHRSKG ...String: GERETWGKKV DFLLSVIGYA VDLGNVWRFP YICYQNGGGA FLLPYTIMAI FGGIPLFYME LALGQYHRNG CISIWRKICP IFKGIGYAI CIIAFYIASY YNTIMAWALY YLISSFTDQL PWTSCKNSWN TGNCTNYFSE DNITWTLHST SPAEEFYTRH V LQIHRSKG LQDLGGISWQ LALCIMLIFT VIYFSIWKGV KTSGKVVWVT ATFPYIILSV LLVRGATLPG AWRGVLFYLK PN WQKLLET GVWIDAAAQI FFSLGPGFGV LLAFASYNKF NNNCYQDALV TSVVNCMTSF VSGFVIFTVL GYMAEMRNED VSE VAKDAG PSLLFITYAE AIANMPASTF FAIIFFLMLI TLGLDSTFAG LEGVITAVLD EFPHVWAKRR ERFVLAVVIT CFFG SLVTL TFGGAYVVKL LEEYATGPAV LTVALIEAVA VSWFYGITQF CRDVKEMLGF SPGWFWRICW VAISPLFLLF IICSF LMSP PQLRLFQYNY PYWSIILGYC IGTSSFICIP TYIAYRLIIT PGTFKERIIK SITPETP |
-Macromolecule #2: heavy chain antibody fragment
Macromolecule | Name: heavy chain antibody fragment / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 12.980533 KDa |
Sequence | String: QVQLQQSGPE LVKLGASVRI SCKASGYRFS YSWMNWVKQR PGKGLEWIGR IYPGDGDTKY SGKFKGKATL TADKSSSTVY MQLSSLTSE DSAVYFCARS AYGSEGFAMD YWGQGTSVT |
-Macromolecule #3: light chain antibody fragment
Macromolecule | Name: light chain antibody fragment / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 11.776065 KDa |
Sequence | String: DIVLTQSPAS LAVSLGQRAT ISCRASESVD NYGISFLNWF QQKPGQPPKL LIYAASNQGS GVPARFSGSG SGTYFSLNIH PMEEDDTAV YFCQQTKGVS WTFGGGTKVE I |
-Macromolecule #4: 3-(5H-DIBENZO[B,F]AZEPIN-5-YL)-N,N-DIMETHYLPROPAN-1-AMINE
Macromolecule | Name: 3-(5H-DIBENZO[B,F]AZEPIN-5-YL)-N,N-DIMETHYLPROPAN-1-AMINE type: ligand / ID: 4 / Number of copies: 1 / Formula: IXX |
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Molecular weight | Theoretical: 280.407 Da |
Chemical component information | ChemComp-IXX: |
-Macromolecule #5: 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-1-benzofuran...
Macromolecule | Name: 5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-1-benzofuran-2-carboxamide type: ligand / ID: 5 / Number of copies: 1 / Formula: YG7 |
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Molecular weight | Theoretical: 441.525 Da |
Chemical component information | ChemComp-YG7: |
-Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 1 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 4 mg/mL | ||||||||||
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Buffer | pH: 8 Component:
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Vitrification | Cryogen name: ETHANE | ||||||||||
Details | monodisperse |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 43.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |