+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-15699 | |||||||||
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Title | Human serotonin 5-HT3A receptor (apo, resting conformation) | |||||||||
Map data | Human serotonin 5-HT3A receptor. Resting conformation. | |||||||||
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 / acetylcholine-gated monoatomic cation-selective channel activity / inorganic cation transmembrane transport / cleavage furrow / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / postsynaptic membrane ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / serotonin binding / acetylcholine-gated monoatomic cation-selective channel activity / inorganic cation transmembrane transport / cleavage furrow / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic 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: 2.98 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 Grønborg 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_15699.map.gz | 59.6 MB | EMDB map data format | |
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Header (meta data) | emd-15699-v30.xml emd-15699.xml | 15.2 KB 15.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_15699_fsc.xml | 8.4 KB | Display | FSC data file |
Images | emd_15699.png | 51 KB | ||
Masks | emd_15699_msk_1.map | 64 MB | Mask map | |
Filedesc metadata | emd-15699.cif.gz | 5.8 KB | ||
Others | emd_15699_half_map_1.map.gz emd_15699_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-15699 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-15699 | HTTPS FTP |
-Related structure data
Related structure data | 8axdMC 8aw2C 8bl8C 8blaC 8blbC 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_15699.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Human serotonin 5-HT3A receptor. Resting conformation. | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.145 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_15699_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Human serotonin 5-HT3A receptor. Resting conformation. Half map B
File | emd_15699_half_map_1.map | ||||||||||||
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Annotation | Human serotonin 5-HT3A receptor. Resting conformation. Half map B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Human serotonin 5-HT3A receptor. Resting conformation. Half map A
File | emd_15699_half_map_2.map | ||||||||||||
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Annotation | Human serotonin 5-HT3A receptor. Resting conformation. Half map A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Human serotonin 5-HT3A receptor
Entire | Name: Human serotonin 5-HT3A receptor |
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Components |
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-Supramolecule #1: Human serotonin 5-HT3A receptor
Supramolecule | Name: Human serotonin 5-HT3A receptor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: apo, resting 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: 62.82182 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MLLWVQQALL ALLLPTLLAQ GEARRSWSHP QFEKGGGSGG GSGGGSWSHP QFEKGGGSGG GSGGGSWSHP QFEKGGGSGG GSGGGSWSH PQFEKENLYF QGSGRNTTRP ALLRLSDYLL TNYRKGVRPV RDWRKPTTVS IDVIVYAILN VDEKNQVLTT Y IWYRQYWT ...String: MLLWVQQALL ALLLPTLLAQ GEARRSWSHP QFEKGGGSGG GSGGGSWSHP QFEKGGGSGG GSGGGSWSHP QFEKGGGSGG GSGGGSWSH PQFEKENLYF QGSGRNTTRP ALLRLSDYLL TNYRKGVRPV RDWRKPTTVS IDVIVYAILN VDEKNQVLTT Y IWYRQYWT DEFLQWNPED FDNITKLSIP TDSIWVPDIL INEFVDVGKS PNIPYVYIRH QGEVQNYKPL QVVTACSLDI YN FPFDVQN CSLTFTSWLH TIQDINISLW RLPEKVKSDR SVFMNQGEWE LLGVLPYFRE FSMESSNYYA EMKFYVVIRR RPL FYVVSL LLPSIFLMVM DIVGFYLPPN SGERVSFKIT LLLGYSVFLI IVSDTLPATA IGTPLIGVYF VVCMALLVIS LAET IFIVR LVHKQDLQQP VPAWLRHLVL ERIAWLLCLR EQSTSQRPPA TSQATKTDDC SAMGNHCSHM GGPQDFEKSP RDRCS PPPP PREASLAVCG LLQELSSIRQ FLEKRDEIRE VARDWLRVGS VLDKLLFHIY LLAVLAYSIT LVMLWSIWQY A 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: |
-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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Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 e/Å2 |