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    General anesthetics predicted to block the GLIC pore with micromolar affinity

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    Genre
    Journal Article
    Date
    2012-05-01
    Author
    LeBard, DN
    Hénin, J
    Eckenhoff, RG
    Klein, ML
    Brannigan, G
    Subject
    Allosteric Site
    Anesthetics, General
    Bacterial Proteins
    Binding Sites
    Computer Simulation
    Cysteine Loop Ligand-Gated Ion Channel Receptors
    Models, Molecular
    Protein Conformation
    Thermodynamics
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/5464
    
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    DOI
    10.1371/journal.pcbi.1002532
    Abstract
    Although general anesthetics are known to modulate the activity of ligand-gated ion channels in the Cys-loop superfamily, there is at present neither consensus on the underlying mechanisms, nor predictive models of this modulation. Viable models need to offer quantitative assessment of the relative importance of several identified anesthetic binding sites. However, to date, precise affinity data for individual sites has been challenging to obtain by biophysical means. Here, the likely role of pore block inhibition by the general anesthetics isoflurane and propofol of the prokaryotic pentameric channel GLIC is investigated by molecular simulations. Microscopic affinities are calculated for both single and double occupancy binding of isoflurane and propofol to the GLIC pore. Computations are carried out for an open-pore conformation in which the pore is restrained to crystallographic radius, and a closed-pore conformation that results from unrestrained molecular dynamics equilibration of the structure. The GLIC pore is predicted to be blocked at the micromolar concentrations for which inhibition by isofluorane and propofol is observed experimentally. Calculated affinities suggest that pore block by propofol occurs at signifcantly lower concentrations than those for which inhibition is observed: we argue that this discrepancy may result from binding of propofol to an allosteric site recently identified by X-ray crystallography, which may cause a competing gain-of-function effect. Affinities of isoflurane and propofol to the allosteric site are also calculated, and shown to be 3 mM for isoflurane and 10μM for propofol; both anesthetics have a lower affinity for the allosteric site than for the unoccupied pore. © 2012 LeBard et al.
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    Public Library of Science (PLoS)
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    PLoS Computational Biology
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    ae974a485f413a2113503eed53cd6c53
    http://dx.doi.org/10.34944/dspace/5446
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