Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation

Cell. 2024 Feb 29;187(5):1160-1176.e21. doi: 10.1016/j.cell.2024.01.032. Epub 2024 Feb 20.


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.

Keywords: cryo-EM; electrophysiology; ligand-gated ion channel; molecular dynamics; neurotransmitter receptor; nicotinic acetylcholine receptor; positive allosteric modulator; structural biology; structure-guided drug design.

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • Cryoelectron Microscopy
  • Humans
  • Inflammation / drug therapy
  • Signal Transduction
  • alpha7 Nicotinic Acetylcholine Receptor* / chemistry
  • alpha7 Nicotinic Acetylcholine Receptor* / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor* / ultrastructure


  • alpha7 Nicotinic Acetylcholine Receptor