Cell [IFM]

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The IFM team provides the first structural interpretation of the allosteric modulation at the α7 nicotinic acetylcholine receptor in collaboration with world-renowned structural biologists and electro physiologists from the University of California San Diego (USA) and the Mayo Clinic College of Medicine and Science in Rochester (USA). These results appeared in Cell (IF 66,85) have important implications for the development of new drug therapies for brain disorders.

Graphical 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 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.

 

Reference:

Sean Burke, Mariia Avstrikova, Coleen Noviello, Nuriya Mukhtasimova, Jean-Pierre Changeux, Ganesh Thakur, Steven Sine, Marco Cecchini and Ryan Hibbs

Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation

Cell 2024, DOI: https://doi.org/10.1016/j.cell.2024.01.032 

Contact:

Marco Cecchini, équipe IFM, Institut de Chimie (UMR 7177).