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- EMDB-72845: Human muscle nAChR FCCMS eP121L ACh, XG-590 bound -

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Basic information

Entry
Database: EMDB / ID: EMD-72845
TitleHuman muscle nAChR FCCMS eP121L ACh, XG-590 bound
Map dataHuman muscle nAChR FCCMS eP121L ACh, XG-590 bound
Sample
  • Complex: Human muscle nicotinic acetylcholine receptor CMS mutants
    • Protein or peptide: Acetylcholine receptor subunit alpha
    • Protein or peptide: Acetylcholine receptor subunit beta
    • Protein or peptide: Acetylcholine receptor subunit delta
    • Protein or peptide: Acetylcholine receptor subunit epsilon
  • Ligand: ACETYLCHOLINE
  • Ligand: N-[(5M)-5-(2-fluoro[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)-1,3-thiazol-2-yl]-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda~6~,2-benzothiazine-3-carboxamide
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water
Keywordshuman muscle / nicotinic acetylcholine receptor / MEMBRANE PROTEIN
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 receptor subunit alpha / Acetylcholine receptor subunit beta / Acetylcholine receptor subunit epsilon / Acetylcholine receptor subunit delta
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.44 Å
AuthorsLi H / Hibbs RE
Funding support United States, 1 items
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 23, 2025-
Header (metadata) releaseAug 5, 2026-
Map releaseAug 5, 2026-
UpdateAug 5, 2026-
Current statusAug 5, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72845.png

Downloads & links

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Map

FileDownload / File: emd_72845.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman muscle nAChR FCCMS eP121L ACh, XG-590 bound
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.94 Å/pix.
x 400 pix.
= 374. Å		0.94 Å/pix.
x 400 pix.
= 374. Å		0.94 Å/pix.
x 400 pix.
= 374. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.935 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.68400574 - 1.2051107
Average (Standard dev.)-0.0005173103 (±0.024153158)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 374.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_72845_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_72845_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human muscle nicotinic acetylcholine receptor CMS mutants

EntireName: Human muscle nicotinic acetylcholine receptor CMS mutants
Components
  • Complex: Human muscle nicotinic acetylcholine receptor CMS mutants
    • Protein or peptide: Acetylcholine receptor subunit alpha
    • Protein or peptide: Acetylcholine receptor subunit beta
    • Protein or peptide: Acetylcholine receptor subunit delta
    • Protein or peptide: Acetylcholine receptor subunit epsilon
  • Ligand: ACETYLCHOLINE
  • Ligand: N-[(5M)-5-(2-fluoro[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)-1,3-thiazol-2-yl]-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda~6~,2-benzothiazine-3-carboxamide
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water

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Supramolecule #1: Human muscle nicotinic acetylcholine receptor CMS mutants

SupramoleculeName: Human muscle nicotinic acetylcholine receptor CMS mutants
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Acetylcholine receptor subunit alpha

MacromoleculeName: Acetylcholine receptor subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.747645 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SEHETRLVAK LFKDYSSVVR PVEDHRQVVE VTVGLQLIQL INVDEVNQIV TTNVRLKQQW VDYNLKWNPD DYGGVKKIHI PSEKIWRPD LVLYNNADGD FAIVKFTKVL LQYTGHITWT PPAIFKSYCE IIVTHFPFDE QNCSMKLGTW TYDGSVVAIN P ESDQPDLS ...String:
SEHETRLVAK LFKDYSSVVR PVEDHRQVVE VTVGLQLIQL INVDEVNQIV TTNVRLKQQW VDYNLKWNPD DYGGVKKIHI PSEKIWRPD LVLYNNADGD FAIVKFTKVL LQYTGHITWT PPAIFKSYCE IIVTHFPFDE QNCSMKLGTW TYDGSVVAIN P ESDQPDLS NFMESGEWVI KESRGWKHSV TYSCCPDTPY LDITYHFVMQ RLPLYFIVNV IIPCLLFSFL TGLVFYLPTD SG EKMTLSI SVLLSLTVFL LVIVELIPST SSAVPLIGKY MLFTMVFVIA SIIITVIVIN THHRSPSTHV MPNWVRKVFI DTI PNIMFF STMKRPSREK QDKKIFTEDI DISDISGKPG PPPMGFHSPL IKHPEVKSAI EGIKYIAETM KSDQESNNAA AEWK YVAMV MDHILLGVFM LVCIIGTLAV FAGRLIELNQ QG

UniProtKB: Acetylcholine receptor subunit alpha

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Macromolecule #2: Acetylcholine receptor subunit beta

MacromoleculeName: Acetylcholine receptor subunit beta / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.84075 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SEAEGRLREK LFSGYDSSVR PAREVGDRVR VSVGLILAQL ISLNEKDEEM STKVYLDLEW TDYRLSWDPA EHDGIDSLRI TAESVWLPD VVLLNNNDGN FDVALDISVV VSSDGSVRWQ PPGIYRSSCS IQVTYFPFDW QNCTMVFSSY SYDSSEVSLQ T GLGPDGQG ...String:
SEAEGRLREK LFSGYDSSVR PAREVGDRVR VSVGLILAQL ISLNEKDEEM STKVYLDLEW TDYRLSWDPA EHDGIDSLRI TAESVWLPD VVLLNNNDGN FDVALDISVV VSSDGSVRWQ PPGIYRSSCS IQVTYFPFDW QNCTMVFSSY SYDSSEVSLQ T GLGPDGQG HQEIHIHEGT FIENGQWEII HKPSRLIQPP GDPRGGREGQ RQEVIFYLII RRKPLFYLVN VIAPCILITL LA IFVFYLP PDAGEKMGLS IFALLTLTVF LLLLADKVPE TSLSVPIIIK YLMFTMVLVT FSVILSVVVL NLHHRSPHTH QMP LWVRQI FIHKLPLYLR LKRPKPERDL MPEPPHCSSP GSGWGRGTDE YFIRKPPSDF LFPKPNRFQP ELSAPDLRRF IDGP NRAVA LLPELREVVS SISYIARQLQ EQEDHDALKE DWQFVAMVVD RLFLWTFIIF TSVGTLVIFL DATYHLPPPD PFPSR

UniProtKB: Acetylcholine receptor subunit beta

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Macromolecule #3: Acetylcholine receptor subunit delta

MacromoleculeName: Acetylcholine receptor subunit delta / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.915359 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LNEEERLIRH LFQEKGYNKE LRPVAHKEES VDVALALTLS NLISLKEVEE TLTTNVWIEH GWTDNRLKWN AEEFGNISVL RLPPDMVWL PEIVLENNND GSFQISYSCN VLVYHYGFVY WLPPAIFRSS CPISVTYFPF DWQNCSLKFS SLKYTAKEIT L SLKQDAKE ...String:
LNEEERLIRH LFQEKGYNKE LRPVAHKEES VDVALALTLS NLISLKEVEE TLTTNVWIEH GWTDNRLKWN AEEFGNISVL RLPPDMVWL PEIVLENNND GSFQISYSCN VLVYHYGFVY WLPPAIFRSS CPISVTYFPF DWQNCSLKFS SLKYTAKEIT L SLKQDAKE NRTYPVEWII IDPEGFTENG EWEIVHRPAR VNVDPRAPLD SPSRQDITFY LIIRRKPLFY IINILVPCVL IS FMVNLVF YLPADSGEKT SVAISVLLAQ SVFLLLISKR LPATSMAIPL IGKFLLFGMV LVTMVVVICV IVLNIHFRTP STH VLSEGV KKLFLETLPE LLHMSRPAED GPSPGALVRR SSSLGYISKA EEYFLLKSRS DLMFEKQSER HGLARRLTTA RRPP ASSEQ AQQELFNELK PAVDGANFIV NHMRDQNNYN EEKDSWNRVA RTVDRLCLFV VTPVMVVGTA WIFLQGVYNQ PPPQP FPGD PYSYNVQDKR FI

UniProtKB: Acetylcholine receptor subunit delta

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Macromolecule #4: Acetylcholine receptor subunit epsilon

MacromoleculeName: Acetylcholine receptor subunit epsilon / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.799336 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KNEELRLYHH LFNNYDPGSR PVREPEDTVT ISLKVTLTNL ISLNEKEETL TTSVWIGIDW QDYRLNYSKD DFGGIETLRV PSELVWLPE IVLENNIDGQ FGVAYDANVL VYEGGSVTWL PLAIYRSVCA VEVTYFPFDW QNCSLIFRSQ TYNAEEVEFT F AVDNDGKT ...String:
KNEELRLYHH LFNNYDPGSR PVREPEDTVT ISLKVTLTNL ISLNEKEETL TTSVWIGIDW QDYRLNYSKD DFGGIETLRV PSELVWLPE IVLENNIDGQ FGVAYDANVL VYEGGSVTWL PLAIYRSVCA VEVTYFPFDW QNCSLIFRSQ TYNAEEVEFT F AVDNDGKT INKIDIDTEA YTENGEWAID FCPGVIRRHH GGATDGPGET DVIYSLIIRR KPLFYVINII VPCVLISGLV LL AYFLPAQ AGGQKCTVSI NVLLAQTVFL FLIAQKIPET SLSVPLLGRF LIFVMVVATL IVMNCVIVLN VSQRTPTTHA MSP RLRHVL LELLPRLLGS PPPPEAPRAA SPPRRASSVG LLLRAEELIL KKPRSELVFE GQRHRQGTWT AAFCQSLGAA APEV RCCVD AVNFVAESTR DQEATGEEVS DWVRMGNALD NICFWAALVL FSVGSSLIFL GAYFNRVPDL PYAPCIQP

UniProtKB: Acetylcholine receptor subunit epsilon

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Macromolecule #8: ACETYLCHOLINE

MacromoleculeName: ACETYLCHOLINE / type: ligand / ID: 8 / Number of copies: 2 / Formula: ACH
Molecular weightTheoretical: 146.207 Da
Chemical component information

ChemComp-ACH:
ACETYLCHOLINE

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Macromolecule #9: N-[(5M)-5-(2-fluoro[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)-1,3-...

MacromoleculeName: N-[(5M)-5-(2-fluoro[1,1'-biphenyl]-4-yl)-4-(trifluoromethyl)-1,3-thiazol-2-yl]-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda~6~,2-benzothiazine-3-carboxamide
type: ligand / ID: 9 / Number of copies: 2 / Formula: A1CVU
Molecular weightTheoretical: 575.554 Da

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Macromolecule #10: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 10 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #11: water

MacromoleculeName: water / type: ligand / ID: 11 / Number of copies: 3 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 7.4
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: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionAlgorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.44 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 210863
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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