+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-15689 | |||||||||
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Title | Mouse serotonin 5-HT3A receptor in complex with vortioxetine | |||||||||
Map data | Mouse serotonin 5-HT3A receptor in complex with vortioxetine | |||||||||
Sample |
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Keywords | Pentameric ligand-gated ion channel / Serotonin receptor / vortioxetine / 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 / excitatory extracellular ligand-gated monoatomic ion channel activity / serotonin binding / inorganic cation transmembrane transport / acetylcholine-gated monoatomic cation-selective channel activity / cleavage furrow / transmembrane transporter complex ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated monoatomic cation channel activity / serotonin-activated cation-selective channel complex / serotonin receptor signaling pathway / excitatory extracellular ligand-gated monoatomic ion channel activity / serotonin binding / inorganic cation transmembrane transport / acetylcholine-gated monoatomic cation-selective channel activity / 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 / presynaptic membrane / postsynaptic membrane / neuron projection / axon / neuronal cell body / glutamatergic synapse / synapse / identical protein binding / plasma membrane Similarity search - Function | |||||||||
Biological species | Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.01 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_15689.map.gz | 49.7 MB | EMDB map data format | |
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Header (meta data) | emd-15689-v30.xml emd-15689.xml | 16.1 KB 16.1 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_15689_fsc.xml | 7.9 KB | Display | FSC data file |
Images | emd_15689.png | 136.9 KB | ||
Masks | emd_15689_msk_1.map | 52.7 MB | Mask map | |
Filedesc metadata | emd-15689.cif.gz | 6.1 KB | ||
Others | emd_15689_half_map_1.map.gz emd_15689_half_map_2.map.gz | 49.1 MB 49.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-15689 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-15689 | HTTPS FTP |
-Validation report
Summary document | emd_15689_validation.pdf.gz | 870.9 KB | Display | EMDB validaton report |
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Full document | emd_15689_full_validation.pdf.gz | 870.4 KB | Display | |
Data in XML | emd_15689_validation.xml.gz | 15.5 KB | Display | |
Data in CIF | emd_15689_validation.cif.gz | 19.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-15689 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-15689 | HTTPS FTP |
-Related structure data
Related structure data | 8aw2MC 8axdC 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_15689.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | Mouse serotonin 5-HT3A receptor in complex with vortioxetine | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.05 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_15689_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: Mouse serotonin 5-HT3A receptor in complex with vortioxetine...
File | emd_15689_half_map_1.map | ||||||||||||
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Annotation | Mouse serotonin 5-HT3A receptor in complex with vortioxetine half map A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Mouse serotonin 5-HT3A receptor in complex with vortioxetine...
File | emd_15689_half_map_2.map | ||||||||||||
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Annotation | Mouse serotonin 5-HT3A receptor in complex with vortioxetine half map B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Mouse serotonin 5-HT3A receptor in complex with vortioxetine
Entire | Name: Mouse serotonin 5-HT3A receptor in complex with vortioxetine |
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Components |
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-Supramolecule #1: Mouse serotonin 5-HT3A receptor in complex with vortioxetine
Supramolecule | Name: Mouse serotonin 5-HT3A receptor in complex with vortioxetine type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: Homopentameric complex of 5-HT3A receptor subunits |
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Source (natural) | Organism: Mus musculus (house mouse) |
-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: Mus musculus (house mouse) |
Molecular weight | Theoretical: 63.765852 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MRLCIPQVLL ALFLSMLTGP GEGSRRRWSH PQFEKGGGSG GGSGGGSWSH PQFEKGGGSG GGSGGGSWSH PQFEKGGGSG GGSGGGSWS HPQFEKENLY FQGSGATQAR DTTQPALLRL SDHLLANYKK GVRPVRDWRK PTTVSIDVIM YAILNVDEKN Q VLTTYIWY ...String: MRLCIPQVLL ALFLSMLTGP GEGSRRRWSH PQFEKGGGSG GGSGGGSWSH PQFEKGGGSG GGSGGGSWSH PQFEKGGGSG GGSGGGSWS HPQFEKENLY FQGSGATQAR DTTQPALLRL SDHLLANYKK GVRPVRDWRK PTTVSIDVIM YAILNVDEKN Q VLTTYIWY RQYWTDEFLQ WTPEDFDNVT KLSIPTDSIW VPDILINEFV DVGKSPNIPY VYVHHRGEVQ NYKPLQLVTA CS LDIYNFP FDVQNCSLTF TSWLHTIQDI NITLWRSPEE VRSDKSIFIN QGEWELLEVF PQFKEFSIDI SNSYAEMKFY VII RRRPLF YAVSLLLPSI FLMVVDIVGF CLPPDSGERV SFKITLLLGY SVFLIIVSDT LPATAIGTPL IGVYFVVCMA LLVI SLAET IFIVRLVHKQ DLQRPVPDWL RHLVLDRAAW ILCLGEQPMA HRPPATFQAN KTDDCSGSDL LPAMGNHCSH VGGPQ DLEK TPRGRGSPLP PPREASLAVR GLLQELSSIR HFLEKRDEMR EVARDWLRVG YVLDRLLFRI YLLAVLAYSI TLVTLW SIW HLW UniProtKB: 5-hydroxytryptamine receptor 3A |
-Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 5 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #5: CHLORIDE ION
Macromolecule | Name: CHLORIDE ION / type: ligand / ID: 5 / Number of copies: 5 / Formula: CL |
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Molecular weight | Theoretical: 35.453 Da |
-Macromolecule #6: Vortioxetine
Macromolecule | Name: Vortioxetine / type: ligand / ID: 6 / 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
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 37.73 e/Å2 |
Electron beam | Acceleration voltage: 300 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: 0.9 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |