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- PDB-8axd: Human serotonin 5-HT3A receptor (apo, resting conformation) -

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Basic information

Entry
Database: PDB / ID: 8axd
TitleHuman serotonin 5-HT3A receptor (apo, resting conformation)
Components5-hydroxytryptamine receptor 3A
KeywordsMEMBRANE PROTEIN / Human pentameric ligand-gated ion channel / Human serotonin receptor
Function / homology
Function and homology information


Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated cation-selective signaling pathway / serotonin-activated cation-selective channel complex / serotonin-gated monoatomic cation channel activity / excitatory extracellular ligand-gated monoatomic ion channel activity / serotonin receptor signaling pathway / transmembrane transporter complex / serotonin binding / : / cleavage furrow ...Neurotransmitter receptors and postsynaptic signal transmission / serotonin-gated cation-selective signaling pathway / serotonin-activated cation-selective channel complex / serotonin-gated monoatomic cation channel activity / excitatory extracellular ligand-gated monoatomic ion channel activity / serotonin receptor signaling pathway / transmembrane transporter complex / serotonin binding / : / cleavage furrow / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / monoatomic ion transmembrane transport / chemical synaptic transmission / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsLopez-Sanchez, U. / Nury, H.
Funding supportEuropean Union, 1items
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, 2022Deposition site: PDBE / Processing site: PDBE
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 5-hydroxytryptamine receptor 3A
B: 5-hydroxytryptamine receptor 3A
C: 5-hydroxytryptamine receptor 3A
D: 5-hydroxytryptamine receptor 3A
E: 5-hydroxytryptamine receptor 3A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)317,33715
Polymers314,1095
Non-polymers3,22810
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area36650 Å2
ΔGint-203 kcal/mol
Surface area85830 Å2
MethodPISA
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "D"
d_5ens_1chain "E"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1THRALAA1 - 397
d_12ens_1NAGNAGF
d_13ens_1NAGNAGA
d_21ens_1THRALAB1 - 397
d_22ens_1NAGNAGG
d_23ens_1NAGNAGB
d_31ens_1THRALAC1 - 397
d_32ens_1NAGNAGH
d_33ens_1NAGNAGC
d_41ens_1THRALAD1 - 397
d_42ens_1NAGNAGI
d_43ens_1NAGNAGD
d_51ens_1THRALAE1 - 397
d_52ens_1NAGNAGJ
d_53ens_1NAGNAGE

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Components

#1: Protein
5-hydroxytryptamine receptor 3A / 5-HT3-A / 5-HT3A / 5-hydroxytryptamine receptor 3 / 5-HT-3 / 5-HT3R / Serotonin receptor 3A / ...5-HT3-A / 5-HT3A / 5-hydroxytryptamine receptor 3 / 5-HT-3 / 5-HT3R / Serotonin receptor 3A / Serotonin-gated ion channel receptor


Mass: 62821.820 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR3A, 5HT3R, HTR3 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P46098
#2: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#3: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human serotonin 5-HT3A receptor / Type: COMPLEX / Details: apo, resting conformation / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 279 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2300 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 104052 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 69.84 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002717055
ELECTRON MICROSCOPYf_angle_d0.477523300
ELECTRON MICROSCOPYf_chiral_restr0.04032745
ELECTRON MICROSCOPYf_plane_restr0.00332835
ELECTRON MICROSCOPYf_dihedral_angle_d3.90132290
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2BELECTRON MICROSCOPYNCS constraints2.92336049101E-12
ens_1d_3CELECTRON MICROSCOPYNCS constraints4.51301897614E-13
ens_1d_4DELECTRON MICROSCOPYNCS constraints8.0841307685E-13
ens_1d_5EELECTRON MICROSCOPYNCS constraints2.80679251593E-12

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