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    Mapping a molecular link between allosteric inhibition and activation of the glycine receptor

    Miller, P.S. and Topf, Maya and Smart, T.G. (2008) Mapping a molecular link between allosteric inhibition and activation of the glycine receptor. Nature Structural & Molecular Biology 15 , pp. 1084-1093. ISSN 1545-9985.

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    Abstract

    Cys-loop ligand-gated ion channels mediate rapid neurotransmission throughout the central nervous system. They possess agonist recognition sites and allosteric sites where modulators regulate ion channel function. Using strychnine-sensitive glycine receptors, we identified a scaffold of hydrophobic residues enabling allosteric communication between glycine-agonist binding loops A and D, and the Zn2+-inhibition site. Mutating these hydrophobic residues disrupted Zn2+ inhibition, generating novel Zn2+-activated receptors and spontaneous channel activity. Homology modeling and electrophysiology revealed that these phenomena are caused by disruption to three residues on the '-' loop face of the Zn2+-inhibition site, and to D84 and D86, on a neighboring beta3 strand, forming a Zn2+-activation site. We provide a new view for the activation of a Cys-loop receptor where, following agonist binding, the hydrophobic core and interfacial loops reorganize in a concerted fashion to induce downstream gating.

    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: 04 Aug 2010 14:09
    Last Modified: 07 Dec 2016 15:02
    URI: http://eprints.bbk.ac.uk/id/eprint/1143

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