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Evidence for Epibatidine Binding to the Desensitization Gate in α7 nAChR from Molecular Dynamics Simulations and
Jesko Kaiser1, Christoph G W Gertzen1,2, Daniel Mann3
1Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
Abstract:
The homopentameric α7-nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel widely expressed in the human nervous system and susceptible to allosteric modulation. A recent cryo-EM structure (EMD 22983; PDB ID 7KOX) revealed unassigned Coulomb density. Unbiased molecular dynamics simulations of buffer components around α7-nAChR show that (±)-epibatidine can occupy not only the orthosteric site but also the pore near the desensitization gate, consistent with the unmodeled Coulomb density and expanding the receptor's pocketome.
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