9yf0 | pdb_00009yf0
Human muscle nAChR SCCMS aV249F ACh, Fluoxetine bound
Structural highlights
DiseaseACHB_HUMAN Slow-channel congenital myasthenic syndrome;Congenital myasthenic syndrome with primary acetylcholine receptor deficiency;Fast-channel congenital myasthenic syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionACHB_HUMAN After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.[1] Publication Abstract from PubMedVoluntary 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(1-3). Mutations in muscle acetylcholine receptors disrupt this process by either impairing (fast-channel) or prolonging (slow-channel) channel openings(1,4). 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(5,6). 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. Correcting congenital myasthenia-associated acetylcholine receptor defects.,Li H, Mukhtasimova N, Teng J, Cavalli ES, Gu X, Sello JK, Sine SM, Hibbs RE Nature. 2026 Jul 1:10.1038/s41586-026-10706-1. doi: 10.1038/s41586-026-10706-1. PMID:42386970[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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