5hcm
The GLIC pentameric Ligand-Gated Ion Channel 2-21' cross-linked mutant complexed to bromoform
Structural highlights
FunctionGLIC_GLOVI Cationic channel with similar permeabilities for Na(+) and K(+), that is activated by an increase of the proton concentration on the extracellular side. Displays no permeability for chloride ions. Shows slow kinetics of activation, no desensitization and a single channel conductance of 8 pS. Might contribute to adaptation to external pH change.[1] Publication Abstract from PubMedPentameric ligand-gated ion channels have been identified as the principal target of general anesthetics (GA), whose molecular mechanism of action remains poorly understood. Bacterial homologs, such as the Gloeobacter violaceus receptor (GLIC), have been shown to be valid functional models of GA action. The GA bromoform inhibits GLIC at submillimolar concentration. We characterize bromoform binding by crystallography and molecular dynamics (MD) simulations. GLIC's open form structure identified three intra-subunit binding sites. We crystallized the locally closed form with an additional bromoform molecule in the channel pore. We systematically compare binding with the multiple potential sites of allosteric channel regulation in the open, locally closed, and resting forms. MD simulations reveal differential exchange pathways between sites from one form to the other. GAs predominantly access the receptor from the lipid bilayer in all cases. Differential binding affinity among the channel forms is observed; the pore site markedly stabilizes the inactive versus active state. Sites of Anesthetic Inhibitory Action on a Cationic Ligand-Gated Ion Channel.,Laurent B, Murail S, Shahsavar A, Sauguet L, Delarue M, Baaden M Structure. 2016 Apr 5;24(4):595-605. doi: 10.1016/j.str.2016.02.014. Epub 2016, Mar 24. PMID:27021161[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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