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  • 1
    Publication Date: 2011-01-21
    Description: General anaesthetics have enjoyed long and widespread use but their molecular mechanism of action remains poorly understood. There is good evidence that their principal targets are pentameric ligand-gated ion channels (pLGICs) such as inhibitory GABA(A) (gamma-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus (GLIC), whose X-ray structure was recently solved, is also sensitive to clinical concentrations of general anaesthetics. Here we describe the crystal structures of the complexes propofol/GLIC and desflurane/GLIC. These reveal a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer. Both molecules establish van der Waals interactions with the protein; propofol binds at the entrance of the cavity whereas the smaller, more flexible, desflurane binds deeper inside. Mutations of some amino acids lining the binding site profoundly alter the ionic response of GLIC to protons, and affect its general-anaesthetic pharmacology. Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects. These data provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nury, Hugues -- Van Renterghem, Catherine -- Weng, Yun -- Tran, Alphonso -- Baaden, Marc -- Dufresne, Virginie -- Changeux, Jean-Pierre -- Sonner, James M -- Delarue, Marc -- Corringer, Pierre-Jean -- R01 GM069379/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jan 20;469(7330):428-31. doi: 10.1038/nature09647.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur, Groupe Recepteurs-Canaux, F-75015 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248852" target="_blank"〉PubMed〈/a〉
    Keywords: Anesthetics, General/*chemistry/*metabolism ; Binding Sites/genetics ; Crystallography, X-Ray ; Cyanobacteria/*chemistry ; Electrophysiological Phenomena ; Isoflurane/*analogs & derivatives/chemistry/metabolism ; Ligand-Gated Ion Channels/*chemistry/genetics/*metabolism ; Ligands ; Models, Molecular ; Molecular Dynamics Simulation ; Mutant Proteins/chemistry/genetics/metabolism ; Propofol/*chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protons
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-07-20
    Description: Pentameric ligand-gated ion channels (pLGICs), which mediate chemo-electric signal transduction in animals, have been recently found in bacteria. Despite clear sequence and 3D structure homology, the phylogenetic distance between prokaryotic and eukaryotic homologs suggests significant structural divergences, especially at the interface between the extracellular (ECD) and the transmembrane (TMD) domains. To challenge this possibility, we constructed a chimera in which the ECD of the bacterial protein GLIC is fused to the TMD of the human α1 glycine receptor (α1GlyR). Electrophysiology in Xenopus oocytes shows that it functions as a proton-gated ion channel, thereby locating the proton activation site(s) of GLIC in its ECD. Patch-clamp experiments in BHK cells show that the ion channel displays an anionic selectivity with a unitary conductance identical to that of the α1GlyR. In addition, pharmacological investigations result in transmembrane allosteric modulation similar to the one observed on α1GlyR. Indeed, the clinically active drugs propofol, four volatile general anesthetics, alcohols, and ivermectin all potentiate the chimera while they inhibit GLIC. Collectively, this work shows the compatibility between GLIC and α1GlyR domains and points to conservation of the ion channel and transmembrane allosteric regulatory sites in the chimera. This provides evidence that GLIC and α1GlyR share a highly homologous 3D structure. GLIC is thus a relevant model of eukaryotic pLGICs, at least from the anionic type. In addition, the chimera is a good candidate for mass production in Escherichia coli, opening the way for investigations of “druggable” eukaryotic allosteric sites by X-ray crystallography.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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