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    Spectroscopic tools for the study of voltage gated sodium channel structure, function and ligand binding

    Colledge, Matthew (2021) Spectroscopic tools for the study of voltage gated sodium channel structure, function and ligand binding. PhD thesis, Birkbeck, University of London.

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    Abstract

    As the proteins responsible for the initiation and propagation of the action potential in excitable cells, voltage-gated sodium channels (NaVs) are crucial drug targets. Antiarrhythmics, anaesthetics, and antiepileptic drugs all target NaVs. Yet despite the difference in NaV subtypes affecting these diseases, the drugs used to treat them are able to act while showing little subtype specificity. This is explained by drugs displaying state-dependant binding and kinetics. Hence an understanding of the structural changes in different gating states of NaVs is vital for structure-based drug design, of more effective and selective compounds. To date there is no atomic-resolution structure of a functional eukaryotic NaV, although the structures of several prokaryotic NaVs which share pharmacological characteristics with their eukaryotic counterparts have been determined. However these structures are in variety of conformations and the relationships between them remain unclear. This study presents biophysical techniques complementary to structural ones to investigate the gating of NaVs, using the channel from Magnetococcus Marinus (NaVMs) as a case study. Oriented circular dichroism (oCD) spectroscopy is used to report on the orientation of the pore-lining α-helices within the membrane, based on quantitative analysis of oCD data. Single molecule FRET spectroscopy is able to measure interatomic distances across biological molecules, and here is used to investigate the changes in pore diameter at the gate of NaVMs. Also presented is a new web-based application which uses protein structure files to define the orientation of α-helices that comprise the channel.

    Metadata

    Item Type: Thesis
    Copyright Holders: The copyright of this thesis rests with the author, who asserts his/her right to be known as such according to the Copyright Designs and Patents Act 1988. No dealing with the thesis contrary to the copyright or moral rights of the author is permitted.
    Depositing User: Acquisitions And Metadata
    Date Deposited: 12 Jul 2021 11:57
    Last Modified: 14 Jul 2021 05:28
    URI: https://eprints.bbk.ac.uk/id/eprint/45073

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