5lg3

X-ray structure of a pentameric ligand gated ion channel from Erwinia chrysanthemi (ELIC) in complex with chlorpromazine

spinqualitylabelsall models 5lg3, resolution 3.57Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5lg3 is a 10 chain structure with sequence from Dickeya dadantii 3937. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: Z80 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function E0SJQ4_DICD3 Publication Abstract from PubMed Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine. Unexpectedly, we do not find a chlorpromazine molecule in the channel pore of ELIC, but behind the beta8-beta9 loop in the extracellular ligand-binding domain. The beta8-beta9 loop is localized downstream from the neurotransmitter binding site and plays an important role in coupling of ligand binding to channel opening. In combination with electrophysiological recordings from ELIC cysteine mutants and a thiol-reactive derivative of chlorpromazine, we demonstrate that chlorpromazine binding at the beta8-beta9 loop is responsible for receptor inhibition. We further use molecular-dynamics simulations to support the X-ray data and mutagenesis experiments. Together, these data unveil an allosteric binding site in the extracellular ligand-binding domain of ELIC. Our results extend on previous observations and further substantiate our understanding of a multisite model for allosteric modulation of Cys-loop receptors. Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine.,Nys M, Wijckmans E, Farinha A, Yoluk O, Andersson M, Brams M, Spurny R, Peigneur S, Tytgat J, Lindahl E, Ulens C Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):E6696-E6703. Epub 2016 Oct 10. PMID:27791038 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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