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- PDB-8aw2: Mouse serotonin 5-HT3A receptor in complex with vortioxetine -

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Basic information

Entry
Database: PDB / ID: 8aw2
TitleMouse serotonin 5-HT3A receptor in complex with vortioxetine
Components5-hydroxytryptamine receptor 3A
KeywordsMEMBRANE PROTEIN / Pentameric ligand-gated ion channel / Serotonin receptor / vortioxetine
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 / serotonin receptor signaling pathway / serotonin binding / : / cleavage furrow / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / postsynaptic membrane / identical protein binding
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 speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 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 29, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 6, 2024Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 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 1.3Oct 16, 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)326,66030
Polymers318,8295
Non-polymers7,83025
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
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_1THRHISA1 - 384
d_12ens_1NAGBMAF
d_13ens_1NAGNAGG
d_14ens_1NAGNAGA
d_15ens_1CLCLQ
d_16ens_1VTXVTXR
d_21ens_1THRHISB1 - 384
d_22ens_1NAGBMAH
d_23ens_1NAGNAGI
d_24ens_1NAGNAGB
d_25ens_1CLCLT
d_26ens_1VTXVTXU
d_31ens_1THRHISC1 - 384
d_32ens_1NAGBMAJ
d_33ens_1NAGNAGK
d_34ens_1NAGNAGC
d_35ens_1CLCLW
d_36ens_1VTXVTXX
d_41ens_1THRHISD1 - 384
d_42ens_1NAGBMAL
d_43ens_1NAGNAGM
d_44ens_1NAGNAGD
d_45ens_1CLCLZ
d_46ens_1VTXVTXAA
d_51ens_1THRHISE1 - 384
d_52ens_1NAGBMAN
d_53ens_1NAGNAGO
d_54ens_1NAGNAGE
d_55ens_1CLCLCA
d_56ens_1VTXVTXDA

NCS oper:
IDCodeMatrixVector
1given(0.309307643978, 0.950962007466, -0.000204288236626), (-0.950962023762, 0.309307611593, -0.000175425781336), (-0.000103635346633, 0.00024853089005, 0.999999963746)-32.7695742523, 206.875782524, -0.0140977334709
2given(0.308651990495, -0.951175007528, 0.000231984568573), (0.951175011074, 0.308652028917, 0.000152817539565), (-0.000216958732113, 0.000173490486813, 0.999999961415)206.929479131, -32.7570642761, 0.0056574319498
3given(-0.809175719308, 0.587566723466, 2.75163734326E-5), (-0.587566715377, -0.809175698318, -0.000210317852046), (-0.000101310190526, -0.000186351804369, 0.999999977505)153.929799026, 302.024905304, 0.0352450237114
4given(-0.808999753158, -0.58780896294, -0.000149928570289), (0.587808946382, -0.808999766606, 0.000142073372538), (-0.000204804180144, 2.68079683791E-5, 0.999999978668)302.021605052, 153.842305746, 0.0303420379383

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Components

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Protein , 1 types, 5 molecules ABCDE

#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: 63765.852 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Htr3a, 5ht3, Htr3 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P23979

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Sugars , 3 types, 15 molecules

#2: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#3: 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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: 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

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Non-polymers , 2 types, 10 molecules

#5: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#6: 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

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Details

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: Mouse serotonin 5-HT3A receptor in complex with vortioxetine
Type: COMPLEX / Details: Homopentameric complex of 5-HT3A receptor subunits / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2300 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 37.73 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM software
IDNameVersionCategory
7PHENIX1.2model fitting
12cryoSPARCv3.3.13D reconstruction
13PHENIX1.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 35013 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 67.26 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004516815
ELECTRON MICROSCOPYf_angle_d0.66422965
ELECTRON MICROSCOPYf_chiral_restr0.04432730
ELECTRON MICROSCOPYf_plane_restr0.00632780
ELECTRON MICROSCOPYf_dihedral_angle_d11.19722355
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2BELECTRON MICROSCOPYNCS constraints3.60323881178E-13
ens_1d_3CELECTRON MICROSCOPYNCS constraints4.83668306114E-12
ens_1d_4DELECTRON MICROSCOPYNCS constraints4.39036290547E-13
ens_1d_5EELECTRON MICROSCOPYNCS constraints6.67281526736E-11

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