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- EMDB-60606: human alpha 7 nicotinic acetylcholine receptor in complex with GA... -

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Basic information

Entry
Database: EMDB / ID: EMD-60606
Titlehuman alpha 7 nicotinic acetylcholine receptor in complex with GAT107 and calcium (open state)
Map data
Sample
  • Complex: human alpha 7 nicotinic acetylcholine receptor in complex with GAT107
    • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
KeywordsLigand-gated ion channel / Positive allosteric modulator / Ago-PAM / Allosteric modulation / Calcium potentiation / 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 / : ...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 / : / 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 / positive regulation of angiogenesis / calcium ion transport / amyloid-beta binding / monoatomic ion transmembrane transport / postsynaptic membrane / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / learning or memory / positive regulation of protein phosphorylation / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.89 Å
AuthorsLiu S / Zheng Y / Tian C
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Discov / Year: 2025
Title: Structural basis for allosteric agonism of human α7 nicotinic acetylcholine receptors.
Authors: Sanling Liu / Yining Zheng / Haopeng Chen / Xin Li / Qipeng Yan / Wenjun Mu / Yaning Fu / Huan Chen / Hongwei Hou / Lei Liu / Changlin Tian /
Abstract: The α7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, α7 ...The α7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, α7 nAChR has different binding sites for different ligands, particularly agonists and positive allosteric modulators (PAMs). Ago-PAMs can both directly activate and allosterically modulate α7 nAChR. However, the mechanism underlying α7 nAChR modulation by ago-PAM has yet to be fully elucidated. Here, we present cryo-EM structures of α7 nAChR in complex with the ago-PAM GAT107 and Ca in the open and desensitized states, respectively. Our results from both structural comparisons and functional assays suggest an allosteric mechanism underlying GAT107 modulation and calcium potentiation of α7 nAChR, involving local conformational changes in the ECD-TMD coupling region and a global structural rearrangement in the transmembrane domain. This work provides a new mechanism of α7 nAChR gating distinct from that of conventional agonist binding. These findings would aid in drug design and enrich our biophysical understanding of pentameric ligand-gated ion channels.
History
DepositionJun 21, 2024-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateApr 23, 2025-
Current statusApr 23, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60606.png

Downloads & links

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Map

FileDownload / File: emd_60606.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 240 pix.
= 256.8 Å		1.07 Å/pix.
x 240 pix.
= 256.8 Å		1.07 Å/pix.
x 240 pix.
= 256.8 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.22
Minimum - Maximum-2.3803837 - 4.172625
Average (Standard dev.)0.0075131194 (±0.10168025)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 256.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_60606_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_60606_half_map_2.map
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Sample components

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Entire : human alpha 7 nicotinic acetylcholine receptor in complex with GAT107

EntireName: human alpha 7 nicotinic acetylcholine receptor in complex with GAT107
Components
  • Complex: human alpha 7 nicotinic acetylcholine receptor in complex with GAT107
    • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION

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Supramolecule #1: human alpha 7 nicotinic acetylcholine receptor in complex with GAT107

SupramoleculeName: human alpha 7 nicotinic acetylcholine receptor in complex with GAT107
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 57.61625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRCSPGGVWL ALAASLLHVS LQGEFQRKLY KELVKNYNPL ERPVANDSQP LTVYFSLSLL QIMDVDEKNQ VLTTNIWLQM SWTDHYLQW NVSEYPGVKT VRFPDGQIWK PDILLYNSAD ERFDATFHTN VLVNSSGHCQ YLPPGIFKSS CYIDVRWFPF D VQHCKLKF ...String:
MRCSPGGVWL ALAASLLHVS LQGEFQRKLY KELVKNYNPL ERPVANDSQP LTVYFSLSLL QIMDVDEKNQ VLTTNIWLQM SWTDHYLQW NVSEYPGVKT VRFPDGQIWK PDILLYNSAD ERFDATFHTN VLVNSSGHCQ YLPPGIFKSS CYIDVRWFPF D VQHCKLKF GSWSYGGWSL DLQMQEADIS GYIPNGEWDL VGIPGKRSER FYECCKEPYP DVTFTVTMRR RTLYYGLNLL IP CVLISAL ALLVFLLPAD SGEKISLGIT VLLSLTVFML LVAEIMPATS DSVPLIAQYF ASTMIIVGLS VVVTVIVLQY HHH DPDGGK MPKWTRVILL NWCAWFLRMK RPGEDKVRPA CQHKQRRCSL ASVEMSAVAP PPASNGNLLY IGFRGLDGVH CVPT PDSGV VCGRMACSPT HDEHLLHGGQ PPEGDPDLAK ILEEVRYIAN RFRCQDESEA VCSEWKFAAC VVDRLCLMAF SVFTI ICTI GILMSAPNFV EAVSKDFAGG DYKDDDDK

UniProtKB: Neuronal acetylcholine receptor subunit alpha-7

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / 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 #4: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 5 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 54.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.7 µm / Nominal defocus min: 1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.89 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 118309
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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