4TNV

C. elegans glutamate-gated chloride channel (GluCl) in complex with Fab in a non-conducting conformation

Summary for 4TNV

• Entry DOI: 10.2210/pdb4tnv/pdb
• Related: 3RHW 3RI5 3RIA 3RIF 4TNW
• Descriptor: Avermectin-sensitive glutamate-gated chloride channel GluCl alpha, Mouse monoclonal Fab fragment, heavy chain, Mouse monoclonal Fab fragment, light chain, ... (7 entities in total)
• Functional Keywords: membrane protein, ligand-gated ion channel, neurotransmitter receptor, cys-loop receptor, transport protein-immune system complex, transport protein/immune system
• Biological source: Caenorhabditis elegans; More
• Total number of polymer chains: 30
• Total formula weight: 878622.71

Authors

Althoff, T.,Hibbs, R.E.,Banerjee, S.,Gouaux, E. (deposition date: 2014-06-05, release date: 2014-08-13, Last modification date: 2024-10-16)

Primary citation

Althoff, T.,Hibbs, R.E.,Banerjee, S.,Gouaux, E.
X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors.
Nature, 512:333-337, 2014

PubMed Abstract: Cys-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.

PubMed: 25143115
DOI: 10.1038/nature13669

Experimental method

X-RAY DIFFRACTION (3.6 Å)