Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization

The α7 nicotinic
acetylcholine receptor (α7nAChR) mediates
signaling in the central nervous system and cholinergic anti-inflammatory
pathways. Ivermectin is a positive allosteric modulator of a full-length
α7nAChR and an agonist of the α7nAChR construct containing
transmembrane (TMD) and intracellular (ICD) domains, but structural
insights of the binding have not previously been determined. Here,
combining nuclear magnetic resonance as a primary experimental tool
with Rosetta comparative modeling and molecular dynamics simulations,
we have revealed details of ivermectin binding to the α7nAChR
TMD + ICD and corresponding structural changes in an ivermectin-induced
desensitized state. Ivermectin binding was stabilized predominantly
by hydrophobic interactions from interfacial residues between adjacent
subunits near the extracellular end of the TMD, where the inter-subunit
gap was substantially expanded in comparison to the apo structure.
The ion-permeation pathway showed a profile distinctly different from
the resting-state profile but similar to profiles of desensitized
α7nAChR. The ICD also exhibited structural changes, including
reorientation of the MX and h3 helices relative to the channel axis.
The resulting structures of the α7nAChR TMD + ICD in complex
with ivermectin provide opportunities for discovering new modulators
of therapeutic potential and exploring the structural basis of cytoplasmic
signaling under different α7nAChR functional states.