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- EMDB-15699: Human serotonin 5-HT3A receptor (apo, resting conformation) -

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Basic information

Entry
Database: EMDB / ID: EMD-15699
TitleHuman serotonin 5-HT3A receptor (apo, resting conformation)
Map dataHuman serotonin 5-HT3A receptor. Resting conformation.
Sample
  • Complex: Human serotonin 5-HT3A receptor
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHuman 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 / inorganic cation transmembrane transport / excitatory extracellular ligand-gated monoatomic ion channel activity / 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 / inorganic cation transmembrane transport / excitatory extracellular ligand-gated monoatomic ion 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 / postsynaptic membrane / neuron projection / synapse / identical protein binding / plasma membrane
Similarity search - Function
5-hydroxytryptamine 3 receptor / 5-hydroxytryptamine 3 receptor, A subunit / : / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel ...5-hydroxytryptamine 3 receptor / 5-hydroxytryptamine 3 receptor, A subunit / : / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain
Similarity search - Domain/homology
5-hydroxytryptamine receptor 3A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsLopez-Sanchez U / Nury H
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)637733European Union
CitationJournal: 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
DepositionAug 31, 2022-
Header (metadata) releaseMar 6, 2024-
Map releaseMar 6, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15699.png

Downloads & links

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Map

FileDownload / File: emd_15699.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman serotonin 5-HT3A receptor. Resting conformation.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 256 pix.
= 293.12 Å		1.15 Å/pix.
x 256 pix.
= 293.12 Å		1.15 Å/pix.
x 256 pix.
= 293.12 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.145 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.8995814 - 2.5655737
Average (Standard dev.)0.0005864493 (±0.06409961)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 293.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_15699_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Human serotonin 5-HT3A receptor. Resting conformation. Half map B

Fileemd_15699_half_map_1.map
AnnotationHuman serotonin 5-HT3A receptor. Resting conformation. Half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Human serotonin 5-HT3A receptor. Resting conformation. Half map A

Fileemd_15699_half_map_2.map
AnnotationHuman serotonin 5-HT3A receptor. Resting conformation. Half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human serotonin 5-HT3A receptor

EntireName: Human serotonin 5-HT3A receptor
Components
  • Complex: Human serotonin 5-HT3A receptor
    • Protein or peptide: 5-hydroxytryptamine receptor 3A
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human serotonin 5-HT3A receptor

SupramoleculeName: Human serotonin 5-HT3A receptor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: apo, resting conformation
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 5-hydroxytryptamine receptor 3A

MacromoleculeName: 5-hydroxytryptamine receptor 3A / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.82182 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration6.0 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 104052
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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