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- PDB-8ci2: human alpha7 nicotinic receptor in complex with the C4 nanobody u... -

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Basic information

Entry
Database: PDB / ID: 8ci2
Titlehuman alpha7 nicotinic receptor in complex with the C4 nanobody under sub-saturating conditions
Components
  • Nanobody C4
  • Neuronal acetylcholine receptor subunit alpha-7
KeywordsMEMBRANE PROTEIN / ion channel nanobody Nicotinic acetylcholine receptor
Function / homology
Function and homology information


sensory processing / synaptic transmission involved in micturition / dendrite arborization / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity / short-term memory ...sensory processing / synaptic transmission involved in micturition / dendrite arborization / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity / short-term memory / cation channel complex / dendritic spine organization / chloride channel regulator activity / acetylcholine binding / regulation of amyloid precursor protein catabolic process / acetylcholine receptor signaling pathway / neurotransmitter receptor complex / positive regulation of amyloid-beta formation / positive regulation of protein metabolic process / negative regulation of amyloid-beta formation / response to amyloid-beta / ligand-gated ion channel signaling pathway / monoatomic ion channel activity / modulation of excitatory postsynaptic potential / plasma membrane raft / negative regulation of tumor necrosis factor production / positive regulation of excitatory postsynaptic potential / toxic substance binding / monoatomic ion transport / negative regulation of canonical NF-kappaB signal transduction / negative regulation of cytokine production involved in inflammatory response / positive regulation of long-term synaptic potentiation / response to nicotine / regulation of membrane potential / excitatory postsynaptic potential / synapse organization / calcium channel activity / cognition / memory / positive regulation of angiogenesis / intracellular calcium ion homeostasis / calcium ion transport / transmembrane signaling receptor activity / amyloid-beta binding / monoatomic ion transmembrane transport / chemical synaptic transmission / postsynaptic membrane / learning or memory / response to hypoxia / positive regulation of ERK1 and ERK2 cascade / postsynapse / neuron projection / positive regulation of MAPK cascade / positive regulation of cell population proliferation / dendrite / synapse / endoplasmic reticulum membrane / signal transduction / protein homodimerization activity / membrane / plasma membrane
Similarity search - Function
Nicotinic acetylcholine receptor / 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
Neuronal acetylcholine receptor subunit alpha-7
Similarity search - Component
Biological speciesHomo sapiens (human)
Vicugna pacos (alpaca)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsPrevost, M.S. / Barilone, N. / Dejean de la Batie, G. / Pons, S. / Ayme, G. / England, P. / Gielen, M. / Bontems, F. / Pehau-Arnaudet, G. / Maskos, U. ...Prevost, M.S. / Barilone, N. / Dejean de la Batie, G. / Pons, S. / Ayme, G. / England, P. / Gielen, M. / Bontems, F. / Pehau-Arnaudet, G. / Maskos, U. / Lafaye, P. / Corringer, P.-J.
Funding supportEuropean Union, France, 5items
OrganizationGrant numberCountry
European Research Council (ERC)788974European Union
Pasteur Institute France
Centre National de la Recherche Scientifique (CNRS) France
iNEXT-DiscoveryEuropean Union
Agence Nationale de la Recherche (ANR)ANR-21-CE37-0026 France
CitationJournal: Nat Commun / Year: 2023
Title: An original potentiating mechanism revealed by the cryo-EM structures of the human α7 nicotinic receptor in complex with nanobodies.
Authors: Marie S Prevost / Nathalie Barilone / Gabrielle Dejean de la Bâtie / Stéphanie Pons / Gabriel Ayme / Patrick England / Marc Gielen / François Bontems / Gérard Pehau-Arnaudet / Uwe Maskos ...Authors: Marie S Prevost / Nathalie Barilone / Gabrielle Dejean de la Bâtie / Stéphanie Pons / Gabriel Ayme / Patrick England / Marc Gielen / François Bontems / Gérard Pehau-Arnaudet / Uwe Maskos / Pierre Lafaye / Pierre-Jean Corringer /
Abstract: The human α7 nicotinic receptor is a pentameric channel mediating cellular and neuronal communication. It has attracted considerable interest in designing ligands for the treatment of neurological ...The human α7 nicotinic receptor is a pentameric channel mediating cellular and neuronal communication. It has attracted considerable interest in designing ligands for the treatment of neurological and psychiatric disorders. To develop a novel class of α7 ligands, we recently generated two nanobodies named E3 and C4, acting as positive allosteric modulator and silent allosteric ligand, respectively. Here, we solved the cryo-electron microscopy structures of the nanobody-receptor complexes. E3 and C4 bind to a common epitope involving two subunits at the apex of the receptor. They form by themselves a symmetric pentameric assembly that extends the extracellular domain. Unlike C4, the binding of E3 drives an agonist-bound conformation of the extracellular domain in the absence of an orthosteric agonist, and mutational analysis shows a key contribution of an N-linked sugar moiety in mediating E3 potentiation. The nanobody E3, by remotely controlling the global allosteric conformation of the receptor, implements an original mechanism of regulation that opens new avenues for drug design.
History
DepositionFeb 8, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 11, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 6, 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
Revision 1.2Jul 9, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 9, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Neuronal acetylcholine receptor subunit alpha-7
B: Neuronal acetylcholine receptor subunit alpha-7
C: Neuronal acetylcholine receptor subunit alpha-7
D: Neuronal acetylcholine receptor subunit alpha-7
E: Neuronal acetylcholine receptor subunit alpha-7
F: Nanobody C4
G: Nanobody C4
I: Nanobody C4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)272,06823
Polymers267,7348
Non-polymers4,33415
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area21390 Å2
ΔGint6 kcal/mol
Surface area67770 Å2
MethodPISA

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Components

#1: Protein
Neuronal acetylcholine receptor subunit alpha-7


Mass: 44050.949 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRNA7, NACHRA7 / Production host: Homo sapiens (human) / References: UniProt: P36544
#2: Antibody Nanobody C4


Mass: 15826.398 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vicugna pacos (alpaca) / Production host: Homo sapiens (human)
#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-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
#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.: 10 / 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

Component
IDNameTypeEntity IDParent-IDSource
1Complex of the human alpha7 nicotinic acetylcholine receptor with the Nanobody C4 and with NicotineCOMPLEX#1-#20MULTIPLE SOURCES
2human alpha7 nicotinic acetylcholine receptorCOMPLEX#11RECOMBINANT
3Nanobody C4COMPLEX#21RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.25 MDaNO
22
33
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Vicugna pacos (alpaca)30538
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Buffer solutionpH: 8
SpecimenConc.: 0.7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 2400 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 29644 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00911559
ELECTRON MICROSCOPYf_angle_d0.95915742
ELECTRON MICROSCOPYf_dihedral_angle_d6.2731639
ELECTRON MICROSCOPYf_chiral_restr0.0491725
ELECTRON MICROSCOPYf_plane_restr0.0072003

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