Voltage-gated sodium channels (Navs) are responsible for the initiation of the action potential in excitable cells. Several prokaryotic sodium channels, most notably NavMs from Magnetococcus marinus and NavAb from Arcobacter butzleri, have been shown to be good models for human sodium channels based on their sequence homologies and high levels of functional similarities, including ion flux, and functional consequences of critical mutations. The complete full-length crystal structures of these prokaryotic sodium channels captured in different functional states have now revealed the molecular natures of changes associated with the gating process. These include the structures of the intracellular gate, the selectivity filter, the voltage sensors, the intra-membrane fenestrations, and the transmembrane (TM) pore. Here we have identified for the first time how changes in the fenestrations in the hydrophobic TM region associated with the opening of the intracellular gate could modulate the state-dependent ingress and binding of drugs in the TM cavity, in a way that could be exploited for rational drug design.
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December 2018
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Dysfunctional cytoskeleton and neurodegeneration: novel pathways in Parkinson's disease? This image represents the degeneration of the neuronal tree during the aging process. In this issue Civiero et al. discuss the consequence of impaired cytoskeletal dynamics on neurite morphology and neuronal physiology in Parkinson's disease. For further details see pages 1653–1663.
Review Article|
October 31 2018
Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design
Giulia Montini;
Giulia Montini
*
1Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1H 0HA, U.K.
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Jennifer Booker;
Jennifer Booker
*
1Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1H 0HA, U.K.
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Altin Sula;
Altin Sula
*
1Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1H 0HA, U.K.
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B.A. Wallace
1Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1H 0HA, U.K.
Correspondence: B.A. Wallace (b.wallace@mail.cryst.bbk.ac.uk)
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Publisher: Portland Press Ltd
Received:
July 20 2018
Revision Received:
September 07 2018
Accepted:
September 10 2018
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem Soc Trans (2018) 46 (6): 1567–1575.
Article history
Received:
July 20 2018
Revision Received:
September 07 2018
Accepted:
September 10 2018
Citation
Giulia Montini, Jennifer Booker, Altin Sula, B.A. Wallace; Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design. Biochem Soc Trans 17 December 2018; 46 (6): 1567–1575. doi: https://doi.org/10.1042/BST20180295
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