4tnv
C. elegans glutamate-gated chloride channel (GluCl) in complex with Fab in a non-conducting conformation
Structural highlights
FunctionGLUCL_CAEEL Glutamate-gated chloride channel subunit; channel properties depend on the subunit composition. Glutamate binding triggers a rapidly reversible current in heteromeric channels formed by glc-1 and glc-2, while the anti-helmintic drug ivermectin and other avermectins trigger a permanently open channel configuration. Channels containing only glc-1 are activated by ivermectin, but not by glutamate alone (in vitro). The heteromeric channel formed by glc-1 and glc-2 is also activated by ibotenate, and it is blocked by picrotoxin and flufenamic acid (PubMed:7935817). Plays a role in the regulation of locomotor behavior (PubMed:16527366).[1] [2] [3] Publication Abstract from PubMedCys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor, high-resolution X-ray structures of extracellular domains and X-ray structures of bacterial orthologues. In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding. However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids. X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors.,Althoff T, Hibbs RE, Banerjee S, Gouaux E Nature. 2014 Aug 21;512(7514):333-7. doi: 10.1038/nature13669. PMID:25143115[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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