Hidden complexity of α7 nicotinic acetylcholine receptor desensitization revealed by MD simulations and Markov state modeling

• 成果类型: Article
• 署名作者: Avstrikova, Mariia; Rodriguez, Paula Milan; Burke, Sean M.; Hibbs, Ryan E.; Changeux, Jean-Pierre; Cecchini, Marco
• 署名单位: Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; Centre National de la Recherche Scientifique (CNRS); CNRS - Institute of Chemistry (INC); University of Texas System; University of Texas Southwestern Medical Center; University of California System; University of California San Diego; Universite PSL; College de France; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13167
• DOI: 10.1073/pnas.2420993122
• 发表日期: 2025-02-18
• 关键词: positive allosteric modulators; gating mechanism; software news; force-field; agonist; subunit; pharmacology; transitions; RESOLUTION; interface

摘要

The alpha 7 nicotinic acetylcholine receptor is a pentameric ligand- gated ion channel that plays an important role in neuronal signaling throughout the nervous system. Its implication in neurological disorders and inflammation has spurred the development of numerous compounds that enhance channel activation. However, the therapeutic potential of these compounds has been limited by the characteristically fast desensitization of the alpha 7 receptor. Using recent high- resolution structures from cryo- EM, and all- atom molecular dynamic simulations augmented by Markov state modeling, here we explore the mechanism of alpha 7 receptor desensitization and its implication on allosteric modulation. The results provide a precise characterization of the desensitization gate and illuminate the mechanism of ion- pore opening/closing with an agonist bound. In addition, the simulations reveal the existence of a short- lived, open- channel intermediate between the activated and desensitized states that rationalizes the paradoxical pharmacology of the L247T mutant and may be relevant to type- II allosteric modulation. This analysis provides an interpretation of the signal transduction mechanism and its regulation in alpha 7 receptors.