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Structure paper

TitleAutoimmune mechanisms elucidated through muscle acetylcholine receptor structures.
Journal, issue, pagesCell, Vol. 188, Issue 9, Page 2390-2406.e20, Year 2025
Publish dateMay 1, 2025
AuthorsHuanhuan Li / Minh C Pham / Jinfeng Teng / Kevin C O'Connor / Colleen M Noviello / Ryan E Hibbs /
PubMed AbstractSkeletal muscle contraction is triggered by acetylcholine (ACh) binding to its ionotropic receptors (AChRs) at neuromuscular junctions. In myasthenia gravis (MG), autoantibodies target AChRs, ...Skeletal muscle contraction is triggered by acetylcholine (ACh) binding to its ionotropic receptors (AChRs) at neuromuscular junctions. In myasthenia gravis (MG), autoantibodies target AChRs, disrupting neurotransmission and causing muscle weakness. While treatments exist, variable patient responses suggest pathogenic heterogeneity. Progress in understanding the molecular basis of MG has been limited by the absence of structures of intact human muscle AChRs. Here, we present high-resolution cryoelectron microscopy (cryo-EM) structures of the human adult AChR in different functional states. Using six MG patient-derived monoclonal antibodies, we mapped distinct epitopes involved in diverse pathogenic mechanisms, including receptor blockade, internalization, and complement activation. Electrophysiological and binding assays revealed how these autoantibodies directly inhibit AChR channel activation. These findings provide critical insights into MG immunopathogenesis, uncovering unrecognized antibody epitope diversity and modes of receptor inhibition, and provide a framework for developing personalized therapies targeting antibody-mediated autoimmune disorders.
External linksCell / PubMed:40203823 / PubMed Central
MethodsEM (single particle)
Resolution1.92 - 2.46 Å
Structure data

47003

9dmg

EMDB-47003, PDB-9dmg:
Human muscle nAChR apo state
Method: EM (single particle) / Resolution: 2.05 Å

47005

9dmh

EMDB-47005, PDB-9dmh:
Human muscle nAChR ACh-bound state
Method: EM (single particle) / Resolution: 2.06 Å

47007

9dmj

EMDB-47007, PDB-9dmj:
Human muscle nAChR with two fab1b-bound
Method: EM (single particle) / Resolution: 2.19 Å

47008

9dmk

EMDB-47008, PDB-9dmk:
Human muscle nAChR with one fab1b-bound
Method: EM (single particle) / Resolution: 2.46 Å

47009

9dml

EMDB-47009, PDB-9dml:
Human muscle nAChR with fab2-bound
Method: EM (single particle) / Resolution: 2.24 Å

47013

9dmq

EMDB-47013, PDB-9dmq:
Human muscle nAChR with fab3-bound
Method: EM (single particle) / Resolution: 2.06 Å

47014

9dms

EMDB-47014, PDB-9dms:
Human muscle nAChR with fab6-bound
Method: EM (single particle) / Resolution: 1.92 Å

47015

9dmt

EMDB-47015, PDB-9dmt:
Human muscle nAChR with fab7-bound
Method: EM (single particle) / Resolution: 2.18 Å

Chemicals

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

ChemComp-MAN:
alpha-D-mannopyranose

ChemComp-CLR:
CHOLESTEROL

ChemComp-ACH:
ACETYLCHOLINE / neurotransmitter*YM

ChemComp-HOH:
WATER

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

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / human muscle / nicotinic acetylcholine receptor

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