51. Principles of activation and permeation in an anion-selective Cys-loop receptor
- Author
-
Ryan E. Hibbs and Eric Gouaux
- Subjects
Agonist ,Anions ,Models, Molecular ,medicine.drug_class ,Allosteric regulation ,Biology ,Neurotransmission ,Neurotransmitter binding ,Article ,chemistry.chemical_compound ,Chloride Channels ,medicine ,Animals ,Receptor ,Caenorhabditis elegans ,Cysteine Loop Ligand-Gated Ion Channel Receptors ,Ions ,Neurotransmitter Agents ,Multidisciplinary ,Binding Sites ,Glutamate receptor ,Protein Structure, Tertiary ,Biochemistry ,chemistry ,Biophysics ,Picrotoxin - Abstract
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 A 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.
- Published
- 2011