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Originally published as Biophys J. BioFAST on April 1, 2005.
doi:10.1529/biophysj.104.050229
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Biophysical Journal 88:3954-3965 (2005)
© 2005 The Biophysical Society

Normal Mode Analysis Suggests a Quaternary Twist Model for the Nicotinic Receptor Gating Mechanism

Antoine Taly *, Marc Delarue {dagger}, Thomas Grutter *, Michael Nilges {ddagger}, Nicolas Le Novère §, Pierre-Jean Corringer * and Jean-Pierre Changeux *

* Récepteurs et Cognition, Unité de Recherche Associeé (URA) Centre National de la Recherche Scientifique 2182, {dagger} Biochimie Structurale, URA Centre National de la Recherche Scientifique 2185, and {ddagger} Bioinformatique Structurale, Institut Pasteur, Paris, France; and § Computational Neurobiology Group, European Molecular Biology Laboratory-European Bioinformatics Institute Hinxton, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom

Correspondence: Address reprint requests to Jean-Pierre Changeux, E-mail: changeux{at}pasteur.fr.

We present a three-dimensional model of the homopentameric {alpha}7 nicotinic acetylcholine receptor (nAChR), that includes the extracellular and membrane domains, developed by comparative modeling on the basis of: 1), the x-ray crystal structure of the snail acetylcholine binding protein, an homolog of the extracellular domain of nAChRs; and 2), cryo-electron microscopy data of the membrane domain collected on Torpedo marmorata nAChRs. We performed normal mode analysis on the complete three-dimensional model to explore protein flexibility. Among the first 10 lowest frequency modes, only the first mode produces a structural reorganization compatible with channel gating: a wide opening of the channel pore caused by a concerted symmetrical quaternary twist motion of the protein with opposing rotations of the upper (extracellular) and lower (transmembrane) domains. Still, significant reorganizations are observed within each subunit, that involve their bending at the domain interface, an increase of angle between the two ß-sheets composing the extracellular domain, the internal ß-sheet being significantly correlated to the movement of the M2 {alpha}-helical segment. This global symmetrical twist motion of the pentameric protein complex, which resembles the opening transition of other multimeric ion channels, reasonably accounts for the available experimental data and thus likely describes the nAChR gating process.




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