Structural highlights
DiseaseACHA7_HUMAN 15q13.3 microdeletion syndrome. FunctionACHA7_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. The channel is blocked by alpha-bungarotoxin. Publication Abstract from PubMedThe alpha7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, alpha7 nAChR has different binding sites for different ligands, particularly agonists and positive allosteric modulators (PAMs). Ago-PAMs can both directly activate and allosterically modulate alpha7 nAChR. However, the mechanism underlying alpha7 nAChR modulation by ago-PAM has yet to be fully elucidated. Here, we present cryo-EM structures of alpha7 nAChR in complex with the ago-PAM GAT107 and Ca(2+) in the open and desensitized states, respectively. Our results from both structural comparisons and functional assays suggest an allosteric mechanism underlying GAT107 modulation and calcium potentiation of alpha7 nAChR, involving local conformational changes in the ECD-TMD coupling region and a global structural rearrangement in the transmembrane domain. This work provides a new mechanism of alpha7 nAChR gating distinct from that of conventional agonist binding. These findings would aid in drug design and enrich our biophysical understanding of pentameric ligand-gated ion channels. Structural basis for allosteric agonism of human alpha7 nicotinic acetylcholine receptors.,Liu S, Zheng Y, Chen H, Li X, Yan Q, Mu W, Fu Y, Chen H, Hou H, Liu L, Tian C Cell Discov. 2025 Apr 8;11(1):35. doi: 10.1038/s41421-025-00788-y. PMID:40195322[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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