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Principles of activation and permeation in an anion-selective Cys-loop receptor

2011; Nature Portfolio; Volume: 474; Issue: 7349 Linguagem: Inglês

10.1038/nature10139

1476-4687

Ryan Hibbs, Eric Gouaux,

Photoreceptor and optogenetics research

Fast inhibitory neurotransmission is essential for nervous system function and is mediated by binding of inhibitory neurotransmitters to receptors of the Cys-loop family embedded in the membranes of neurons. Neurotransmitter binding triggers a conformational change in the receptor, opening an intrinsic chloride channel and thereby dampening neuronal excitability. Here we present the first three-dimensional structure, to our knowledge, of an inhibitory anion-selective Cys-loop receptor, the homopentameric Caenorhabditis elegans glutamate-gated chloride channel α (GluCl), at 3.3 Å resolution. The X-ray structure of the GluCl–Fab complex was determined with the allosteric agonist ivermectin and in additional structures with the endogenous neurotransmitter l-glutamate and the open-channel blocker picrotoxin. Ivermectin, used to treat river blindness, binds in the transmembrane domain of the receptor and stabilizes an open-pore conformation. Glutamate binds in the classical agonist site at subunit interfaces, and picrotoxin directly occludes the pore near its cytosolic base. GluCl provides a framework for understanding mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors. The atomic resolution structure of the glutamate-gated chloride channel (GluCl) from Caenorhabditis elegans has been determined, in the presence of the allosteric agonist ivermectin, the endogenous neurotransmitter L-glutamate and the open-channel blocker picrotoxin. These structures provide a framework for understanding mechanisms of the fast inhibitory neurotransmission that is essential for nervous system function.