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

The alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) mediates signaling in the central nervous system and cholinergic anti-inflammatory pathways. Ivermectin is a positive allosteric modulator of a full-length alpha 7nAChR and an agonist of the alpha 7nAChR 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 alpha 7nAChR 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 alpha 7nAChR. The ICD also exhibited structural changes, including reorientation of the MX and h3 helices relative to the channel axis. The resulting structures of the alpha 7nAChR 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 alpha 7nAChR functional states.

Automated summary

This study reveals the binding details and structural changes induced by Ivermectin in the alpha 7nAChR using nuclear magnetic resonance, comparative modeling, and molecular dynamics simulations. The binding of Ivermectin to the alpha 7nAChR is stabilized by hydrophobic interactions between adjacent subunits, resulting in an expanded inter-subunit gap. The ion-permeation pathway shows a profile similar to the desensitized alpha 7nAChR, providing insights into cytoplasmic signaling under different functional states.