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- EMDB-16598: Human alpha7 nicotinic receptor in complex with the E3 nanobody -

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Basic information

Entry
Database: EMDB / ID: EMD-16598
TitleHuman alpha7 nicotinic receptor in complex with the E3 nanobody
Map data
Sample
  • Complex: complex of the human alpha7 nicotinic acetylcholine receptor with the nanobody E3
    • Complex: human alpha7 nicotinic acetylcholine receptor
      • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
    • Complex: Nanobody E3
      • Protein or peptide: Nanobody E3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsion channel nanobody Nicotinic acetylcholine receptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


sensory processing / dendrite arborization / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine-gated channel complex / regulation of amyloid fibril formation / short-term memory / positive regulation of CoA-transferase activity / acetylcholine receptor activity / dendritic spine organization ...sensory processing / dendrite arborization / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine-gated channel complex / regulation of amyloid fibril formation / short-term memory / positive regulation of CoA-transferase activity / acetylcholine receptor activity / dendritic spine organization / chloride channel regulator activity / acetylcholine binding / regulation of amyloid precursor protein catabolic process / acetylcholine receptor signaling pathway / acetylcholine-gated monoatomic cation-selective channel activity / positive regulation of amyloid-beta formation / negative regulation of amyloid-beta formation / plasma membrane raft / modulation of excitatory postsynaptic potential / positive regulation of excitatory postsynaptic potential / response to amyloid-beta / negative regulation of tumor necrosis factor production / toxic substance binding / monoatomic ion transport / monoatomic ion transmembrane transport / positive regulation of protein metabolic process / positive regulation of long-term synaptic potentiation / synapse organization / response to nicotine / calcium channel activity / memory / cognition / intracellular calcium ion homeostasis / positive regulation of angiogenesis / calcium ion transport / monoatomic ion channel activity / amyloid-beta binding / postsynapse / postsynaptic membrane / positive regulation of MAPK cascade / learning or memory / positive regulation of ERK1 and ERK2 cascade / response to hypoxia / neuron projection / positive regulation of protein phosphorylation / synapse / positive regulation of cell population proliferation / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsPrevost MS / Barilone N / Dejean de la Batie G / Pons S / Ayme G / England P / Gielen M / Bontems F / Pehau-Arnaudet G / Maskos U ...Prevost MS / 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, 5 items
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 1, 2023-
Header (metadata) releaseOct 11, 2023-
Map releaseOct 11, 2023-
UpdateOct 11, 2023-
Current statusOct 11, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16598.png

Downloads & links

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Map

FileDownload / File: emd_16598.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.731 Å
Density
Contour LevelBy AUTHOR: 0.0045
Minimum - Maximum-0.010849908 - 0.033491924
Average (Standard dev.)0.0001261016 (±0.0009806731)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 292.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_16598_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_16598_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : complex of the human alpha7 nicotinic acetylcholine receptor with...

EntireName: complex of the human alpha7 nicotinic acetylcholine receptor with the nanobody E3
Components
  • Complex: complex of the human alpha7 nicotinic acetylcholine receptor with the nanobody E3
    • Complex: human alpha7 nicotinic acetylcholine receptor
      • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
    • Complex: Nanobody E3
      • Protein or peptide: Nanobody E3
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: complex of the human alpha7 nicotinic acetylcholine receptor with...

SupramoleculeName: complex of the human alpha7 nicotinic acetylcholine receptor with the nanobody E3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: human alpha7 nicotinic acetylcholine receptor

SupramoleculeName: human alpha7 nicotinic acetylcholine receptor / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Nanobody E3

SupramoleculeName: Nanobody E3 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Vicugna pacos (alpaca)

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Macromolecule #1: Neuronal acetylcholine receptor subunit alpha-7

MacromoleculeName: Neuronal acetylcholine receptor subunit alpha-7 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.050949 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EFQRKLYKEL VKNYNPLERP VANDSQPLTV YFSLSLLQIM DVDEKNQVLT TNIWLQMSWT DHYLQWNVSE YPGVKTVRFP DGQIWKPDI LLYNSADERF DATFHTNVLV NSSGHCQYLP PGIFKSSCYI DVRWFPFDVQ HCKLKFGSWS YGGWSLDLQM Q EADISGYI ...String:
EFQRKLYKEL VKNYNPLERP VANDSQPLTV YFSLSLLQIM DVDEKNQVLT TNIWLQMSWT DHYLQWNVSE YPGVKTVRFP DGQIWKPDI LLYNSADERF DATFHTNVLV NSSGHCQYLP PGIFKSSCYI DVRWFPFDVQ HCKLKFGSWS YGGWSLDLQM Q EADISGYI PNGEWDLVGI PGKRSERFYE CCKEPYPDVT FTVTMRRRTL YYGLNLLIPC VLISALALLV FLLPADSGEK IS LGITVLL SLTVFMLLVA EIMPATSDSV PLIAQYFAST MIIVGLSVVV TVIVLQYHHH DPDGGKMPKW TRVILLNWCA WFL RMKRDG VAVCSEWKFA ACVVDRLCLM AFSVFTIICT IGILMSAPNF VEAVSKDFAS AGLTETSQVA PA

UniProtKB: Neuronal acetylcholine receptor subunit alpha-7, Neuronal acetylcholine receptor subunit alpha-7

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Macromolecule #2: Nanobody E3

MacromoleculeName: Nanobody E3 / type: protein_or_peptide / ID: 2 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 15.740189 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AVQLQASGGG LVQAGDSLRL SCAASGGTFS HYAVGWFRQA PGKEREFVAA ISWSGRSTSF ANSVKGRFTI SRDSAKNTAY LQMNNLKPE DTAVYCCAPA RFGTGSAARD EYDDCGQGTQ VTVSSAAAEQ KLISEEDLNG AAHHHHHHGS

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 49462
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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