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Yorodumi- EMDB-16105: Human serotonin 5-HT3A receptor in complex with vortioxetine (nan... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-16105 | |||||||||
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Title | Human serotonin 5-HT3A receptor in complex with vortioxetine (nanodiscs, ECD, active/distorted conformation) | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Human pentameric ligand-gated ion channel / Human serotonin receptor / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / serotonin binding / excitatory extracellular ligand-gated monoatomic ion channel activity / inorganic cation transmembrane transport / cleavage furrow / transmembrane transporter complex / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / serotonin binding / excitatory extracellular ligand-gated monoatomic ion channel activity / inorganic cation transmembrane transport / cleavage furrow / transmembrane transporter complex / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / postsynaptic membrane / neuron projection / synapse / identical protein binding / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Lopez-Sanchez U / Nury H | |||||||||
Funding support | European Union, 1 items
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Citation | Journal: Nat Struct Mol Biol / Year: 2024 Title: Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT receptors. Authors: Uriel López-Sánchez / Lachlan Jake Munro / Lucy Kate Ladefoged / Anders Juel Pedersen / Christian Colding Brun / Signe Meisner Lyngby / Delphine Baud / Céline Juillan-Binard / Miriam ...Authors: Uriel López-Sánchez / Lachlan Jake Munro / Lucy Kate Ladefoged / Anders Juel Pedersen / Christian Colding Brun / Signe Meisner Lyngby / Delphine Baud / Céline Juillan-Binard / Miriam Grønlund Pedersen / Sarah C R Lummis / Benny Bang-Andersen / Birgit Schiøtt / Christophe Chipot / Guy Schoehn / Jacques Neyton / Francois Dehez / Hugues Nury / Anders S Kristensen / Abstract: Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT receptor ...Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT receptor (5-HTR), which features two properties: VTX acts differently on rodent and human 5-HTR, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HTR and an agonist-bound-like state of human 5-HTR, in line with the functional profile of the drug. We report four human 5-HTR structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_16105.map.gz | 59.5 MB | EMDB map data format | |
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Header (meta data) | emd-16105-v30.xml emd-16105.xml | 15 KB 15 KB | Display Display | EMDB header |
Images | emd_16105.png | 108.2 KB | ||
Filedesc metadata | emd-16105.cif.gz | 5.8 KB | ||
Others | emd_16105_half_map_1.map.gz emd_16105_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-16105 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-16105 | HTTPS FTP |
-Validation report
Summary document | emd_16105_validation.pdf.gz | 1019.8 KB | Display | EMDB validaton report |
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Full document | emd_16105_full_validation.pdf.gz | 1019.4 KB | Display | |
Data in XML | emd_16105_validation.xml.gz | 12.4 KB | Display | |
Data in CIF | emd_16105_validation.cif.gz | 14.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-16105 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-16105 | HTTPS FTP |
-Related structure data
Related structure data | 8blbMC 8aw2C 8axdC 8bl8C 8blaC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_16105.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.14 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_16105_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_16105_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Human 5HT3A receptor in complex with vortioxetine
Entire | Name: Human 5HT3A receptor in complex with vortioxetine |
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Components |
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-Supramolecule #1: Human 5HT3A receptor in complex with vortioxetine
Supramolecule | Name: Human 5HT3A receptor in complex with vortioxetine / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 Details: (nanodiscs, ECD only, active/distorted conformation) |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: 5-hydroxytryptamine receptor 3A
Macromolecule | Name: 5-hydroxytryptamine receptor 3A / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 52.172324 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: TTRPALLRLS DYLLTNYRKG VRPVRDWRKP TTVSIDVIVY AILNVDEKNQ VLTTYIWYRQ YWTDEFLQWN PEDFDNITKL SIPTDSIWV PDILINEFVD VGKSPNIPYV YIRHQGEVQN YKPLQVVTAC SLDIYNFPFD VQNCSLTFTS WLHTIQDINI S LWRLPEKV ...String: TTRPALLRLS DYLLTNYRKG VRPVRDWRKP TTVSIDVIVY AILNVDEKNQ VLTTYIWYRQ YWTDEFLQWN PEDFDNITKL SIPTDSIWV PDILINEFVD VGKSPNIPYV YIRHQGEVQN YKPLQVVTAC SLDIYNFPFD VQNCSLTFTS WLHTIQDINI S LWRLPEKV KSDRSVFMNQ GEWELLGVLP YFREFSMESS NYYAEMKFYV VIRRRPLFYV VSLLLPSIFL MVMDIVGFYL PP NSGERVS FKITLLLGYS VFLIIVSDTL PATAIGTPLI GVYFVVCMAL LVISLAETIF IVRLVHKQDL QQPVPAWLRH LVL ERIAWL LCLREQSTSQ RPPATSQATK TDDCSAMGNH CSHMGGPQDF EKSPRDRCSP PPPPREASLA VCGLLQELSS IRQF LEKRD EIREVARDWL RVGSVLDKLL FHIYLLAVLA YSITLVMLWS IWQYA UniProtKB: 5-hydroxytryptamine receptor 3A |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #4: Vortioxetine
Macromolecule | Name: Vortioxetine / type: ligand / ID: 4 / Number of copies: 5 / Formula: VTX |
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Molecular weight | Theoretical: 298.446 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 6.0 mg/mL |
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Buffer | pH: 7.4 |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | TFS GLACIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm |
-Image processing
Startup model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 31911 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |