Structural highlights
DiseaseACHA7_HUMAN 15q13.3 microdeletion syndrome. FunctionC562_ECOLX Electron-transport protein of unknown function.ACHA7_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 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 alpha7 agonists, but their potentiation mechanisms remain unclear. Here, we present high-resolution structures of alpha7-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 alpha7 allosteric modulation and activation with implications across the pentameric receptor superfamily. , PMID:38382524[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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