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    Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism

    Bagneris, Claire and DeCaen, P.G. and Naylor, Claire E. and Pryde, D.C. and Nobeli, Irilenia and Clapham, D.E. and Wallace, Bonnie A. (2014) Prokaryotic NavMs channel as a structural and functional model for eukaryotic sodium channel antagonism. Proceedings of the National Academy of Sciences of the United States of America 111 (23), pp. 8428-8433. ISSN 0027-8424.

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    Abstract

    Voltage-gated sodium channels are important targets for the development of pharmaceutical drugs, because mutations in different human sodium channel isoforms have causal relationships with a range of neurological and cardiovascular diseases. In this study, functional electrophysiological studies show that the prokaryotic sodium channel from Magnetococcus marinus (NavMs) binds and is inhibited by eukaryotic sodium channel blockers in a manner similar to the human Nav1.1 channel, despite millions of years of divergent evolution between the two types of channels. Crystal complexes of the NavMs pore with several brominated blocker compounds depict a common antagonist binding site in the cavity, adjacent to lipid-facing fenestrations proposed to be the portals for drug entry. In silico docking studies indicate the full extent of the blocker binding site, and electrophysiology studies of NavMs channels with mutations at adjacent residues validate the location. These results suggest that the NavMs channel can be a valuable tool for screening and rational design of human drugs.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Bioinformatics, Bloomsbury Centre for, Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 27 May 2014 11:34
    Last Modified: 07 Dec 2016 15:00
    URI: http://eprints.bbk.ac.uk/id/eprint/9799

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