Structural Basis for Xenon Inhibition in a Cationic Pentameric Ligand Gated Ion Channel
GLIC receptor is a bacterial pentameric ligand gated ion channel whose action is inhibited by xenon. Xenon has been used in clinical practice as a potent gaseous anaesthetic for decades, but the molecular mechanism of interactions with its integral membrane receptor targets remains poorly understood. Here we characterize by X ray crystallography the xenon binding sites within both the open and "locally closed" (inactive) conformations of GLIC. Major binding sites of xenon, which differ between the two conformations, were identified in three distinct regions that all belong to the trans membrane domain of GLIC: 1) in an intra subunit cavity, 2) at the interface between adjacent subunits, and 3) in the pore. The pore site is unique to the locally closed form where the binding of xenon effectively seals the channel. A putative mechanism of the inhibition of GLIC by xenon is proposed, which might be extended to other pentameric cationic ligand gated ion channels.
PloS one