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- PDB-8bla: Human serotonin 5-HT3A receptor in complex with vortioxetine (det... -

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Basic information

Entry
Database: PDB / ID: 8bla
TitleHuman serotonin 5-HT3A receptor in complex with vortioxetine (detergent, ECD only, active/distorted 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: 3.3 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
DepositionNov 9, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 15, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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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)238,77225
Polymers231,9305
Non-polymers6,84220
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "D"
d_2ens_1chain "B"
d_3ens_1chain "C"
d_4ens_1chain "A"
d_5ens_1chain "E"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg label comp-IDEnd label comp-IDLabel asym-IDLabel seq-ID
d_11ens_1ARGARGD1 - 211
d_12ens_1NAGNAGD
d_13ens_1NAGNAGD
d_14ens_1NAGNAGD
d_15ens_1NAGNAGD
d_16ens_1NAGNAGD
d_17ens_1VTXVTXD
d_21ens_1ARGARGH1 - 211
d_22ens_1NAGNAGI
d_23ens_1NAGNAGJ
d_24ens_1NAGNAGK
d_25ens_1NAGNAGL
d_26ens_1NAGNAGM
d_27ens_1VTXVTXN
d_31ens_1ARGARGO1 - 211
d_32ens_1NAGNAGP
d_33ens_1NAGNAGQ
d_34ens_1NAGNAGR
d_35ens_1NAGNAGS
d_36ens_1NAGNAGT
d_37ens_1VTXVTXU
d_41ens_1ARGARGA1 - 211
d_42ens_1NAGNAGB
d_43ens_1NAGNAGC
d_44ens_1NAGNAGD
d_45ens_1NAGNAGE
d_46ens_1NAGNAGF
d_47ens_1VTXVTXG
d_51ens_1ARGARGE1 - 211
d_52ens_1NAGNAGE
d_53ens_1NAGNAGE
d_54ens_1NAGNAGE
d_55ens_1NAGNAGE
d_56ens_1NAGNAGE
d_57ens_1VTXVTXE

NCS oper:
IDCodeMatrixVector
1given(-0.809104568026, 0.587664668914, -0.000186841818881), (-0.587664673345, -0.809104585579, -3.6021138777E-5), (-0.000172342923028, 8.06554685302E-5, 0.999999981896)179.81791686, 352.813987216, 0.00627660739728
2given(0.308649008063, 0.951175877485, -0.000489808933998), (-0.951175999101, 0.308649015757, -6.16959301203E-5), (9.24953649178E-5, 0.000484936889797, 0.99999987814)-38.2090735026, 241.798727508, -0.0911186817434
3given(-0.807122054372, -0.590384109101, 0.00077010861717), (0.590384009945, -0.80712240739, -0.000374554821165), (0.000842703135445, 0.000152348356764, 0.999999633321)352.899690131, 179.143389836, -0.132422655026
4given(0.308769552271, -0.951136842978, 0.000263667897884), (0.951136878106, 0.308769524811, -0.000140196656596), (5.19335938135E-5, 0.000294072720137, 0.999999955412)241.741170828, -38.2524701294, -0.0531652778581

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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: 46386.031 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR3A, 5HT3R, HTR3 / 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.: 10
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
#4: Chemical
ChemComp-VTX / Vortioxetine / 1-[2-(2,4-dimethylphenyl)sulfanylphenyl]piperazine / 1-(2-((2,4-Dimethylphenyl)thio)phenyl)piperazine


Mass: 298.446 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C18H22N2S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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, active/disorted 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

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 42033 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 64.94 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029675
ELECTRON MICROSCOPYf_angle_d0.4761320
ELECTRON MICROSCOPYf_dihedral_angle_d13.6951385
ELECTRON MICROSCOPYf_chiral_restr0.0451490
ELECTRON MICROSCOPYf_plane_restr0.0051620
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2DELECTRON MICROSCOPYNCS constraints1.87334998774E-13
ens_1d_3DELECTRON MICROSCOPYNCS constraints5.09035486494E-12
ens_1d_4DELECTRON MICROSCOPYNCS constraints2.29735291347E-13
ens_1d_5DELECTRON MICROSCOPYNCS constraints1.63135700728E-10

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