biostudies-literatureBurke SMNIDA NIH HHSNINDS NIH HHSNational Institutes of HealthNIGMS NIH HHS1160-1176.e21https://www.ebi.ac.uk/biostudies/studies/S-EPMC10950261biostudies-literatureUnknown187(5)The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.CellStructural mechanisms of α7 nicotinic receptor allosteric modulation and activation.PMC10950261R37 NS031744U24 GM129547R01 GM057481F31 DA059092T32 GM131963R01 NS031744Burke SMChangeux JPSine SMCecchini MHibbs REThakur GAAvstrikova MMukhtasimova NNoviello CMfalseStructural mechanisms of α7 nicotinic receptor allosteric modulation and activation.The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of α7-modulator complexes, revealing partially overlapping binding sites but varying conformational states. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. We extend the study using a time-resolved cryoelectron microscopy (cryo-EM) approach to reveal asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.2024-01-01T00:00:00Z2024 Feb2026-06-02T10:24:18.49Z2025-04-06T08:33:03.833ZS-EPMC109502613838252410.1016/j.cell.2024.01.032