Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism. - Archive ouverte HAL Access content directly
Journal Articles Biophysical Journal Year : 2005

Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism.

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Antoine Taly
Thomas Grutter
Michael Nilges

Abstract

We present a three-dimensional model of the homopentameric alpha7 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 beta-sheets composing the extracellular domain, the internal beta-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.

Dates and versions

pasteur-00162514 , version 1 (13-07-2007)

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Cite

Antoine Taly, Marc Delarue, Thomas Grutter, Michael Nilges, Nicolas Le Novere, et al.. Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism.. Biophysical Journal, 2005, 88 (6), pp.3954-65. ⟨10.1529/biophysj.104.050229⟩. ⟨pasteur-00162514⟩
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