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- PDB-9yek: Human muscle nAChR SCCMS eL269F ACh, Reboxetine bound (lower 2) -

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Basic information

Entry
Database: PDB / ID: 9yek
TitleHuman muscle nAChR SCCMS eL269F ACh, Reboxetine bound (lower 2)
Components(Acetylcholine receptor subunit ...) x 4
KeywordsMEMBRANE PROTEIN / human muscle / nicotinic acetylcholine receptor
Function / homology
Function and homology information


postsynaptic membrane organization / musculoskeletal movement / skeletal muscle tissue growth / Highly sodium permeable postsynaptic acetylcholine nicotinic receptors / Highly calcium permeable nicotinic acetylcholine receptors / neuromuscular synaptic transmission / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / behavioral response to nicotine ...postsynaptic membrane organization / musculoskeletal movement / skeletal muscle tissue growth / Highly sodium permeable postsynaptic acetylcholine nicotinic receptors / Highly calcium permeable nicotinic acetylcholine receptors / neuromuscular synaptic transmission / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / behavioral response to nicotine / acetylcholine-gated monoatomic cation-selective channel activity / muscle cell development / acetylcholine receptor signaling pathway / muscle cell cellular homeostasis / monoatomic cation transmembrane transporter activity / acetylcholine binding / neuromuscular process / nervous system process / neuron cellular homeostasis / postsynaptic specialization membrane / synaptic transmission, cholinergic / neuromuscular junction development / membrane depolarization / monoatomic cation transport / ligand-gated monoatomic ion channel activity / neuronal action potential / skeletal muscle contraction / muscle contraction / presynaptic modulation of chemical synaptic transmission / response to nicotine / neuromuscular junction / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / regulation of membrane potential / transmembrane signaling receptor activity / presynapse / channel activity / chemical synaptic transmission / monoatomic ion transmembrane transport / postsynaptic membrane / neuron projection / synapse / cell surface / signal transduction / plasma membrane
Similarity search - Function
Nicotinic acetylcholine receptor / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channel transmembrane region / 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
: / ACETYLCHOLINE / Acetylcholine receptor subunit alpha / Acetylcholine receptor subunit beta / Acetylcholine receptor subunit epsilon / Acetylcholine receptor subunit delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.68 Å
AuthorsLi, H. / Hibbs, R.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) United States
CitationJournal: Nature / Year: 2026
Title: Correcting congenital myasthenia-associated acetylcholine receptor defects.
Authors: Huanhuan Li / Nuriya Mukhtasimova / Jinfeng Teng / Elfie S Cavalli / Xilin Gu / Jason K Sello / Steven M Sine / Ryan E Hibbs /
Abstract: Voluntary muscle contraction is triggered by the neurotransmitter acetylcholine binding its receptors on the postsynaptic membrane of the neuromuscular junction, opening ion channels that allow ...Voluntary muscle contraction is triggered by the neurotransmitter acetylcholine binding its receptors on the postsynaptic membrane of the neuromuscular junction, opening ion channels that allow cation influx and initiate depolarization. Mutations in muscle acetylcholine receptors disrupt this process by either impairing (fast-channel) or prolonging (slow-channel) channel openings. These defects cause congenital myasthenic syndromes (CMS), characterized by severe muscle weakness that is often present at birth and, in some cases, progresses to paralysis and death. The structural mechanisms underlying these pathogenic defects and their pharmacological correction remain unknown. Here, using cryogenic electron microscopy, chemical biology and electrophysiology, we determined the structures and functional consequences of representative CMS mutant receptors with and without drugs. In fast-channel disease-associated mutants, we discovered a cryptic allosteric site targeted by positive modulators that restore gating in a mutation-specific manner. In receptor mutants associated with slow-channel disease, quinidine, fluoxetine and reboxetine act as pore blockers; notably, the antidepressant reboxetine selectively blocks desensitized receptors in a mutation-independent fashion, suggesting repurposing potential. Mechanistically, fast-channel mutations uncouple agonist binding from gating, whereas slow-channel mutations stabilize an abnormally widened, desensitized-like pore. These findings reveal unifying principles of CMS pathogenesis and provide a framework for precision therapies.
History
DepositionSep 24, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 5, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 5, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 5, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 5, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 5, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 5, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Acetylcholine receptor subunit alpha
C: Acetylcholine receptor subunit alpha
E: Acetylcholine receptor subunit beta
D: Acetylcholine receptor subunit delta
B: Acetylcholine receptor subunit epsilon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)268,80114
Polymers264,0695
Non-polymers4,7339
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Acetylcholine receptor subunit ... , 4 types, 5 molecules ACEDB

#1: Protein Acetylcholine receptor subunit alpha


Mass: 49747.645 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRNA1, ACHRA, CHNRA / Production host: Homo sapiens (human) / References: UniProt: P02708
#2: Protein Acetylcholine receptor subunit beta


Mass: 54840.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRNB1, ACHRB, CHRNB / Production host: Homo sapiens (human) / References: UniProt: P11230
#3: Protein Acetylcholine receptor subunit delta


Mass: 56915.359 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRND, ACHRD / Production host: Homo sapiens (human) / References: UniProt: Q07001
#4: Protein Acetylcholine receptor subunit epsilon


Mass: 52817.309 Da / Num. of mol.: 1 / Mutation: L269F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHRNE, ACHRE / Production host: Homo sapiens (human) / References: UniProt: Q04844

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Sugars , 4 types, 6 molecules

#5: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#6: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#10: 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.: 1 / 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

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Non-polymers , 3 types, 5 molecules

#8: Chemical ChemComp-ACH / ACETYLCHOLINE


Mass: 146.207 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H16NO2 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-A1D9Y / (2~{S})-2-[(~{S})-(2-ethoxyphenoxy)-phenyl-methyl]morpholine / Esreboxetine


Mass: 313.391 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23NO3
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Details

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: Human muscle nicotinic acetylcholine receptor CMS mutants
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.68 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 39554 / Algorithm: FOURIER SPACE / Symmetry type: POINT
RefinementHighest resolution: 2.68 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00316792
ELECTRON MICROSCOPYf_angle_d0.55822908
ELECTRON MICROSCOPYf_dihedral_angle_d4.4932205
ELECTRON MICROSCOPYf_chiral_restr0.0442657
ELECTRON MICROSCOPYf_plane_restr0.0052872

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