1. On the functional annotation of open-channel structures in the glycine receptor
- Author
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Marco Cecchini, Adrien H. Cerdan, Institut de Chimie de Strasbourg, Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Récepteurs Canaux - Channel Receptors, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The research was supported by the French National Research Agency (ANR-18-CE11-0015) and the European Union’s Horizon 2020 Framework Program for Research and Innovation under the Specific Grant Agreement no. 785907, and Human Brain Project SGA2. This work was granted access to the HPC resources of CCRT/CINES under the allocation 2019-[A0070706644] made by GENCI (Grand Equipement National de Calcul Intensif). Access to HPC resources of the University of Strasbourg (Mesocentre) is gratefully acknowledged., ANR-18-CE11-0015,PENTA_CONTROL,Étude de la dynamique structurale d'un canal ionique pentamérique pour la conception rationnelle des médicaments(2018), European Project: 785907,H2020,HBP SGA2(2018), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Neurobiologie intégrative des Systèmes cholinergiques / Integrative Neurobiology of Cholinergic Systems (NISC), and Sorbonne Université (SU)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
- Subjects
pentameric ligand-gated ion channels ,Protein Conformation ,[SDV]Life Sciences [q-bio] ,neurotransmitter receptors ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Synaptic Transmission ,01 natural sciences ,Ion ,03 medical and health sciences ,Molecular dynamics ,Receptors, Glycine ,Neurotransmitter receptor ,Catalytic Domain ,0103 physical sciences ,structural biology ,Humans ,Lipid bilayer ,Molecular Biology ,Glycine receptor ,Ion channel ,030304 developmental biology ,0303 health sciences ,Binding Sites ,010304 chemical physics ,Chemistry ,030302 biochemistry & molecular biology ,Cryoelectron Microscopy ,Computational Biology ,Conductance ,molecular dynamics simulations ,Electrophysiological Phenomena ,Open-channel flow ,Electrophysiology ,Structural biology ,Functional annotation ,Biophysics ,channel conductance ,glycine receptor ,computational electrophysiology - Abstract
The glycine receptor (GlyR) is by far the best-characterized pentameric ligand-gated ion channel with several high-resolution structures from X-ray crystallography, cryo-EM and modeling. Nonetheless, the significance of the currently available open-pore conformations is debated due to their diversity in the pore geometry. Here, we discuss the physiological significance of existing models of the GlyR active state based on conductance and selectivity measurements by computational electrophysiology. The results support the conclusion that the original cryo-EM reconstruction of the active state obtained in detergents as well as its subsequent refinement by Molecular Dynamics simulations are likely to be non-physiological as they feature artificially dilated ion pores. In addition, the calculations indicate that a physiologically relevant open pore configuration should be constricted within a radius of 2.5 and 2.8Å, which is consistent with previous modeling, electrophysiology measurements, and the most recent cryo-EM structures obtained in a native lipid-membrane environment.
- Published
- 2020