Journal of Biological Chemistry
Spurny, R.; Billen, B.; Howard, R. J.; Brams, M.; Debaveye, S.; Price, K. L.; Weston, D. A.; Strelkov, S. V.; Tytgat, J.; Bertrand, S.; Bertrand, D.; Lummis, S. C. R.; Ulens, C., Multisite Binding of a General Anesthetic to the Prokaryotic Pentameric Erwinia chrysanthemi Ligand-gated Ion Channel (ELIC). J. Biol. Chem. 2013, 288 (12), 8355-8364.
Pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine, glycine, γ-aminobutyric acid GABAA/C receptors, and the Gloeobacter violaceus ligand-gated ion channel (GLIC), are receptors that contain multiple allosteric binding sites for a variety of therapeutics, including general anesthetics. Here, we report the x-ray crystal structure of the Erwinia chrysanthemi ligand-gated ion channel (ELIC) in complex with a derivative of chloroform, which reveals important features of anesthetic recognition, involving multiple binding at three different sites. One site is located in the channel pore and equates with a noncompetitive inhibitor site found in many pLGICs. A second transmembrane site is novel and is located in the lower part of the transmembrane domain, at an interface formed between adjacent subunits. A third site is also novel and is located in the extracellular domain in a hydrophobic pocket between the β7–β10 strands. Together, these results extend our understanding of pLGIC modulation and reveal several specific binding interactions that may contribute to modulator recognition, further substantiating a multisite model of allosteric modulation in this family of ion channels.
Anesthesia, cys-loop, receptors, ion channels, membrane proteins, x-ray, crystallography ELIC, ligand-gated ion channels