Structural 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. [Display omitted] • Positive modulators bind to a site between subunits in the transmembrane domain • Modulator class differences correlate with the stable rotation of a key gating residue • Time-resolved cryo-EM reveals asymmetric state transitions • Allosteric agonists trigger a unique gating cycle Structural interrogation of α7 nicotinic receptor positive modulation clarifies class-specific differences, reveals unique properties of the α7 subtype, and supports a conserved potentiation mechanism among related ion channels. [ABSTRACT FROM AUTHOR]