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- EMDB-16534: human alpha7 nicotinic receptor in complex with the C4 nanobody a... -

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Basic information

Entry
Database: EMDB / ID: EMD-16534
Titlehuman alpha7 nicotinic receptor in complex with the C4 nanobody and nicotine
Map data
Sample
  • Complex: Complex of the human alpha7 nicotinic acetylcholine receptor withthe Nanobody C4 and with Nicotine
    • Complex: human alpha7 nicotinic acetylcholine receptor
      • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
    • Complex: Nanobody C4
      • Protein or peptide: Nanobody C4
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE
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 receptor activity / acetylcholine-gated channel complex / short-term memory / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity / positive regulation of CoA-transferase activity ...sensory processing / dendrite arborization / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / short-term memory / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity / positive regulation of CoA-transferase activity / dendritic spine organization / acetylcholine binding / chloride channel regulator activity / regulation of amyloid precursor protein catabolic process / acetylcholine receptor signaling pathway / positive regulation of amyloid-beta formation / negative regulation of amyloid-beta formation / modulation of excitatory postsynaptic potential / response to amyloid-beta / monoatomic ion channel activity / negative regulation of tumor necrosis factor production / positive regulation of excitatory postsynaptic potential / plasma membrane raft / toxic substance binding / monoatomic ion transport / positive regulation of protein metabolic process / positive regulation of long-term synaptic potentiation / excitatory postsynaptic potential / response to nicotine / synapse organization / calcium channel activity / memory / cognition / intracellular calcium ion homeostasis / calcium ion transport / positive regulation of angiogenesis / amyloid-beta binding / monoatomic ion transmembrane transport / postsynaptic membrane / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / positive regulation of protein phosphorylation / learning or memory / response to hypoxia / postsynapse / neuron projection / positive regulation of cell population proliferation / synapse / signal transduction / protein homodimerization activity / membrane / plasma membrane
Similarity search - Function
Nicotinic acetylcholine receptor / 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
Neuronal acetylcholine receptor subunit alpha-7
Similarity search - Component
Biological speciesHomo sapiens (human) / Vicugna pacos (alpaca)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 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
DepositionJan 24, 2023-
Header (metadata) releaseOct 11, 2023-
Map releaseOct 11, 2023-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16534.png

Downloads & links

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Map

FileDownload / File: emd_16534.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 300 pix.
= 258. Å		0.86 Å/pix.
x 300 pix.
= 258. Å		0.86 Å/pix.
x 300 pix.
= 258. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00248
Minimum - Maximum-0.0068200743 - 0.018412672
Average (Standard dev.)0.000069709 (±0.0007114999)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 258.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_16534_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_16534_half_map_2.map
Projections & Slices
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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 withthe Nanobody C4 and with Nicotine
Components
  • Complex: Complex of the human alpha7 nicotinic acetylcholine receptor withthe Nanobody C4 and with Nicotine
    • Complex: human alpha7 nicotinic acetylcholine receptor
      • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
    • Complex: Nanobody C4
      • Protein or peptide: Nanobody C4
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE

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

SupramoleculeName: Complex of the human alpha7 nicotinic acetylcholine receptor withthe Nanobody C4 and with Nicotine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 250 KDa

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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 C4

SupramoleculeName: Nanobody C4 / 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: 55.36768 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 RMKRPG EDKVRPACQH KQRRCSLASV EMSAVAPPPA SNGNLLYIGF RGLDGVHCVP TPDSGVVCGR MACSPTHDEH LLHG GQPPE GDPDLAKILE EVRYIANRFR CQDESEAVCS EWKFAACVVD RLCLMAFSVF TIICTIGILM SAPNFVEAVS KDFAS AGLT ETSQVAPA

UniProtKB: Neuronal acetylcholine receptor subunit alpha-7

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Macromolecule #2: Nanobody C4

MacromoleculeName: Nanobody C4 / type: protein_or_peptide / ID: 2 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 15.826398 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
AQVQLVESGG GLVQAGGSLK LSCAASGFTF AHYAMVWFRQ APGKEREFVA GISWSGASTY YASSVKGRFT ISRDNAKNTV YLQMNSLKP EDTAVYYVAA ARFGVGVDDD YSYWGQGTQV TVSSAAEQKL ISEEDLNGAA HHHHHHGS

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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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Macromolecule #5: (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE

MacromoleculeName: (S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE / type: ligand / ID: 5 / Number of copies: 5 / Formula: NCT
Molecular weightTheoretical: 162.232 Da
Chemical component information

ChemComp-NCT:
(S)-3-(1-METHYLPYRROLIDIN-2-YL)PYRIDINE / alkaloid*YM

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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

Concentration0.7 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON III (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: 2.2 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 reconstructionApplied symmetry - Point group: C5 (5 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 73690
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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