[English] 日本語
Yorodumi
- PDB-8blb: Human serotonin 5-HT3A receptor in complex with vortioxetine (nan... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8blb
TitleHuman serotonin 5-HT3A receptor in complex with vortioxetine (nanodiscs, ECD, 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 / inorganic cation transmembrane transport / 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 / inorganic cation transmembrane transport / 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 transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / 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 transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / 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 1.2Oct 9, 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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)267,70425
Polymers260,8625
Non-polymers6,84220
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area22720 Å2
ΔGint-24 kcal/mol
Surface area45900 Å2
MethodPISA

-
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: 52172.324 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-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
#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

-
Experimental details

-
Experiment

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

-
Sample preparation

ComponentName: Human 5HT3A receptor in complex with vortioxetine / Type: COMPLEX
Details: (nanodiscs, ECD only, active/distorted 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

-
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)

-
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: 31911 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029675
ELECTRON MICROSCOPYf_angle_d0.46913205
ELECTRON MICROSCOPYf_dihedral_angle_d13.2711385
ELECTRON MICROSCOPYf_chiral_restr0.0461490
ELECTRON MICROSCOPYf_plane_restr0.0051620

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more