Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures

Skeletal muscle contraction is mediated 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. Despite available treatments, patient responses vary, suggesting pathogenic heterogeneity. Current information on molecular mechanisms of autoantibodies is limited due to the absence of structures of an intact human muscle AChR. Here, we overcome challenges in receptor purification and present high-resolution cryo-EM structures of the human adult AChR in different functional states. Using a panel of 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 further defined how these autoantibodies impair AChR function. These findings provide critical insights into MG immunopathology, revealing previously unrecognized antibody epitope diversity and mechanisms of receptor inhibition, offering a foundation for personalized therapies targeting antibody-mediated autoimmune disorders. HighlightsO_LIHuman adult muscle AChR receptor structures in resting and desensitized states C_LIO_LIEpitope mapping for mechanistically distinct pathogenic MG autoantibodies C_LIO_LIStructural and functional elucidation of different inhibition mechanisms in MG C_LI