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- PDB-9iiv: human alpha 7 nicotinic acetylcholine receptor in complex with GA... -

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Basic information

Entry
Database: PDB / ID: 9iiv
Titlehuman alpha 7 nicotinic acetylcholine receptor in complex with GAT107 and calcium (open state)
ComponentsNeuronal acetylcholine receptor subunit alpha-7
KeywordsMEMBRANE PROTEIN / Ligand-gated ion channel / Positive allosteric modulator / Ago-PAM / Allosteric modulation / Calcium potentiation
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 / negative regulation of amyloid-beta formation / positive regulation of protein metabolic process / modulation of excitatory postsynaptic potential / response to amyloid-beta / monoatomic ion channel activity / ligand-gated ion channel signaling pathway / 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 / excitatory postsynaptic potential / regulation of membrane potential / response to nicotine / synapse organization / calcium channel activity / cognition / memory / intracellular calcium ion homeostasis / positive regulation of angiogenesis / calcium ion transport / transmembrane signaling receptor activity / amyloid-beta binding / monoatomic ion transmembrane transport / chemical synaptic transmission / postsynaptic membrane / response to hypoxia / learning or memory / positive regulation of ERK1 and ERK2 cascade / postsynapse / neuron projection / positive regulation of MAPK cascade / positive regulation of cell population proliferation / synapse / dendrite / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.89 Å
AuthorsLiu, S. / Zheng, Y. / Tian, C.
Funding support1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 23, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)292,61625
Polymers288,0815
Non-polymers4,53420
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Neuronal acetylcholine receptor subunit alpha-7


Mass: 57616.250 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRNA7, NACHRA7 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P36544
#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.: 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
#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.: 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
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Ca
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

ComponentName: human alpha 7 nicotinic acetylcholine receptor in complex with GAT107
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1700 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 54 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.89 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118309 / Symmetry type: POINT
RefinementCross valid method: NONE

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