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

Article

关键词: X-RAY-STRUCTURE;    NICOTINIC ACETYLCHOLINE-RECEPTOR;    GATED CHLORIDE CHANNEL;    NEUROMUSCULAR-JUNCTION;    CRYSTAL-STRUCTURE;    BINDING PROTEIN;    LIGAND-BINDING;    ION CHANNELS;    SUBUNIT;    IVERMECTIN;   

DOI  :  10.1038/nature10139

来源: SCIE

【 摘 要 】

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 alpha (GluCl), at 3.3 angstrom 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.

【 授权许可】

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