The article explores the structural mechanisms underlying α7 nicotinic receptor allosteric modulation and activation. The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel crucial for cholinergic signaling in the nervous system. It is a promising therapeutic target due to its role in neurological disorders and inflammation, but its rapid desensitization limits traditional agonists. Positive allosteric modulators (PAMs) enhance neurotransmitter activation without activating the receptor, offering a more effective therapeutic approach. The study presents high-resolution structures of α7-PAM complexes, revealing overlapping binding sites and varying conformational states. Structural and computational analyses suggest that differences in modulator activity arise from the stable rotation of a key gating residue. Time-resolved cryo-EM reveals asymmetric state transitions, and allosteric agonists trigger a unique gating cycle. The results define mechanisms of α7 allosteric modulation and activation, with implications for the pentameric receptor superfamily. Type I and type II PAMs bind overlapping sites within the transmembrane domain, with type II PAMs extending the lifetime of the activated state by slowing desensitization. Allosteric agonists (ago-PAMs) differ by both enhancing neurotransmitter activation and allosterically activating the receptor in the absence of neurotransmitter. Structural analysis shows that modulator activity is regulated by residues in the M2 and M3 helices, with specific residues like N213, M253, and A275 playing key roles in modulator selectivity. Modulator classes stabilize distinct pore conformations, with type I PAMs associated with desensitized states and type II PAMs with expanded pore conformations. The L9' residue in the M2 helix is crucial for modulator activity and channel activation, with its rotation out of the pore stabilizing the activated state. The study also reveals that ago-PAMs, such as GAT107, activate the channel through a unique gating cycle, directly activating the channel and potentiating subsequent neurotransmitter responses. The findings highlight the importance of structural insights in understanding modulator binding sites, ligand recognition, and modulation mechanisms. The study underscores the value of α7 as a model system for investigating allosteric modulation and provides a foundation for developing targeted therapies for neurological disorders. The results also emphasize the need for further research to fully understand the conformational states and asymmetric transitions of α7 receptors.The article explores the structural mechanisms underlying α7 nicotinic receptor allosteric modulation and activation. The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel crucial for cholinergic signaling in the nervous system. It is a promising therapeutic target due to its role in neurological disorders and inflammation, but its rapid desensitization limits traditional agonists. Positive allosteric modulators (PAMs) enhance neurotransmitter activation without activating the receptor, offering a more effective therapeutic approach. The study presents high-resolution structures of α7-PAM complexes, revealing overlapping binding sites and varying conformational states. Structural and computational analyses suggest that differences in modulator activity arise from the stable rotation of a key gating residue. Time-resolved cryo-EM reveals asymmetric state transitions, and allosteric agonists trigger a unique gating cycle. The results define mechanisms of α7 allosteric modulation and activation, with implications for the pentameric receptor superfamily. Type I and type II PAMs bind overlapping sites within the transmembrane domain, with type II PAMs extending the lifetime of the activated state by slowing desensitization. Allosteric agonists (ago-PAMs) differ by both enhancing neurotransmitter activation and allosterically activating the receptor in the absence of neurotransmitter. Structural analysis shows that modulator activity is regulated by residues in the M2 and M3 helices, with specific residues like N213, M253, and A275 playing key roles in modulator selectivity. Modulator classes stabilize distinct pore conformations, with type I PAMs associated with desensitized states and type II PAMs with expanded pore conformations. The L9' residue in the M2 helix is crucial for modulator activity and channel activation, with its rotation out of the pore stabilizing the activated state. The study also reveals that ago-PAMs, such as GAT107, activate the channel through a unique gating cycle, directly activating the channel and potentiating subsequent neurotransmitter responses. The findings highlight the importance of structural insights in understanding modulator binding sites, ligand recognition, and modulation mechanisms. The study underscores the value of α7 as a model system for investigating allosteric modulation and provides a foundation for developing targeted therapies for neurological disorders. The results also emphasize the need for further research to fully understand the conformational states and asymmetric transitions of α7 receptors.