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- PDB-9j37: Cryo-EM structure of human Alpha-7 nicotinic acetylcholine receptor -

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Basic information

Entry
Database: PDB / ID: 9j37
TitleCryo-EM structure of human Alpha-7 nicotinic acetylcholine receptor
ComponentsNeuronal acetylcholine receptor subunit alpha-7
KeywordsMEMBRANE PROTEIN / Receptors / Inhibitor
Function / homology
Function and homology information


sensory processing / dendrite arborization / synaptic transmission involved in micturition / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / chloride channel regulator activity / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity ...sensory processing / dendrite arborization / synaptic transmission involved in micturition / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / chloride channel regulator activity / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity / short-term memory / acetylcholine receptor signaling pathway / dendritic spine organization / acetylcholine binding / regulation of amyloid precursor protein catabolic process / positive regulation of amyloid-beta formation / synaptic transmission, cholinergic / response to amyloid-beta / negative regulation of amyloid-beta formation / positive regulation of protein metabolic process / negative regulation of tumor necrosis factor production / modulation of excitatory postsynaptic potential / plasma membrane raft / monoatomic ion channel activity / monoatomic ion transport / toxic substance binding / negative regulation of cytokine production involved in inflammatory response / excitatory postsynaptic potential / positive regulation of excitatory postsynaptic potential / negative regulation of canonical NF-kappaB signal transduction / positive regulation of long-term synaptic potentiation / response to nicotine / memory / regulation of membrane potential / synapse organization / intracellular calcium ion homeostasis / cognition / positive regulation of angiogenesis / calcium channel activity / calcium ion transport / transmembrane signaling receptor activity / amyloid-beta binding / chemical synaptic transmission / monoatomic ion transmembrane transport / response to hypoxia / positive regulation of MAPK cascade / learning or memory / positive regulation of ERK1 and ERK2 cascade / postsynaptic membrane / postsynapse / neuron projection / 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
CHOLESTEROL / Neuronal acetylcholine receptor subunit alpha-7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYu, R. / Zhao, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82122064 China
CitationJournal: Acta Pharm Sin B / Year: 2026
Title: Deep learning-driven discovery and mechanism of action study of a minimalist conopeptide targeting 7 nicotinic acetylcholine receptor.
Authors: Jinghui Zhang / Zhengji Yin / Yue Li / Cheng Ge / Zixuan Zhang / Pu Yuan / Tao Jiang / David J Craik / Yan Zhao / Rilei Yu /
Abstract: Despite extensive structural and functional characterization of the 7 nicotinic acetylcholine receptor, valuable structural insights into its interactions with conopeptides remain limited, thereby ...Despite extensive structural and functional characterization of the 7 nicotinic acetylcholine receptor, valuable structural insights into its interactions with conopeptides remain limited, thereby hindering the rational development of peptide-based modulators for this clinically important receptor subtype. Here, we present an integrated pipeline combining deep learning, structural biology, computational modeling and electrophysiology to accelerate the discovery and optimization of 7 nAChR-targeting conopeptides. To overcome data scarcity, we developed a deep learning model using the ESM-2 protein language framework, enabling efficient screening of 689 disulfide-poor conopeptides. This approach identified SS1, a novel antagonist of 7 nAChR, which was systematically optimized structure-activity relationship studies to yield [ΔQP,S8R]SS1-a minimalist peptide with nanomolar potency (IC = 49.2 nmol/L), enhanced selectivity, and improved stability. Cryo-EM and computational modeling resolved the 3.3 Å resolution structure of 7 nAChR bound to [S8R]SS1, revealing a unique binding mode stabilized by hydrogen bonds, hydrophobic interactions, and glycan contacts, while hybrid receptor conformations (closed/desensitized) elucidated its inhibitory mechanism. This work establishes a transformative deep learning-to-experiment framework for accelerating the discovery and optimization of nature-inspired peptide therapeutics.
History
DepositionAug 8, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release
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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)276,21920
Polymers271,0575
Non-polymers5,16115
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: 54211.445 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: 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: obtained synthetically
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.: 5 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
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-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: AChR7 nicotinic acetylcholine receptor / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 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: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59900 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00216410
ELECTRON MICROSCOPYf_angle_d0.51822420
ELECTRON MICROSCOPYf_dihedral_angle_d4.8592260
ELECTRON MICROSCOPYf_chiral_restr0.042615
ELECTRON MICROSCOPYf_plane_restr0.0052745

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