Crystal Structure of the Monomeric Extracellular Domain of α9 Nicotinic Receptor Subunit in Complex With α-Conotoxin RgIA: Molecular Dynamics Insights Into RgIA Binding to α9α10 Nicotinic Receptors

Conclusion The first crystal structure of a human nAChR domain with an α-Ctx is presented. The structure revealed the interactions between α-Ctx RgIA and the (+) side of neuronal nAChR α9-ECD in high detail. Based on the structure of this complex, models of human α9α10 nAChR ECD with fully formed binding sites were constructed with RgIA bound to each of them. Our MD simulations suggest that the favorable binding site of RgIA in the human α9α10 nAChR ECD consists of either α9 or α10 subunits as the (+) side and of an adjacent α9 rather than α10 subunit as the (−) side. The results of this study may be helpful to medicinal chemists for design of improved RgIA analogs targeting the human α9α10 nAChR against auditory diseases and neuropathic pain. Author Contributions MZ and PG conceived the project, expressed and purified α9-ECD, conducted the competition experiments, crystallized the complex of α9-ECD with α-Ctx RgIA and solved the crystal structure. PG, MZ, and IK designed the experiments. II and IK synthesized and purified the α-Ctx RgIA and AP performed and analyzed the MD simulations. PG, MZ, and AP wrote the manuscript. ST and VT contributed to management of the project and edited the manuscript. All authors reviewed and approved the manuscript. Funding This work was supported by a grant from Stavros Niarchos Foundation (ST and MZ), by RSF (Gra...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research