9YEX
Human muscle nAChR SCCMS bV266M ACh, Quinidine bound
Summary for 9YEX
| Entry DOI | 10.2210/pdb9yex/pdb |
| EMDB information | 72866 |
| Descriptor | Acetylcholine receptor subunit alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose, Acetylcholine receptor subunit beta, ... (11 entities in total) |
| Functional Keywords | human muscle, nicotinic acetylcholine receptor, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 268648.21 |
| Authors | |
| Primary citation | Li, H.,Mukhtasimova, N.,Teng, J.,Cavalli, E.S.,Gu, X.,Sello, J.K.,Sine, S.M.,Hibbs, R.E. Correcting congenital myasthenia-associated acetylcholine receptor defects. Nature, 2026 Cited by PubMed 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 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. PubMed: 42386970DOI: 10.1038/s41586-026-10706-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.47 Å) |
Structure validation
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