3p50

Structure of propofol bound to a pentameric ligand-gated ion channel, GLIC

spinqualitylabelsall models 3p50, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3p50 is a 5 chain structure with sequence from Gloeobacter violaceus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.3Å Ligands: LMT, PFL, PLC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GLIC_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. Publication Abstract from PubMed 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. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel.,Nury H, Van Renterghem C, Weng Y, Tran A, Baaden M, Dufresne V, Changeux JP, Sonner JM, Delarue M, Corringer PJ Nature. 2011 Jan 20;469(7330):428-31. PMID:21248852 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ion channels 3D structures

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