8V86

Alpha7-nicotinic acetylcholine receptor bound to GAT107

Summary for 8V86

• Entry DOI: 10.2210/pdb8v86/pdb
• Related: 8UT1 8UTB 8UZJ 8V80 8V82 8V88 8V89 8V8A 8V8C 8V8D
• EMDB information: 43025
• Descriptor: Neuronal acetylcholine receptor subunit alpha-7,Soluble cytochrome b562, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: ion channel, membrane protein, nicotinic receptor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 354616.07

Authors

Burke, S.M.,Noviello, C.M.,Hibbs, R.E. (deposition date: 2023-12-04, release date: 2024-02-21, Last modification date: 2024-10-16)

Primary citation

Burke, S.M.,Avstrikova, M.,Noviello, C.M.,Mukhtasimova, N.,Changeux, J.P.,Thakur, G.A.,Sine, S.M.,Cecchini, M.,Hibbs, R.E.
Structural mechanisms of alpha 7 nicotinic receptor allosteric modulation and activation.
Cell, 187:1160-1176.e21, 2024

PubMed Abstract: 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.

PubMed: 38382524
DOI: 10.1016/j.cell.2024.01.032

Experimental method

ELECTRON MICROSCOPY (2.47 Å)