Structural Basis for Ion Permeation Mechanism in Pentameric Ligand-Gated Ion Channels

Abstract

Structural studies of ion permeation in pentameric ligand-gated ion channels (pLGIC) need higher resolution crystal structures. We have solved the structure of an open form of GLIC, a prokaryotic pLGIC, at 2.4 Å. It reveals two clearly resolved water pentagons with one sodium ion between them: a self-stabilized ice-like water pentagon at the level of Ser 6' and a second wider water pentagon at the level of Thr 2’, in continuous exchange with Glu −2'. Computational methods predict that the position of the ice-like “tight” pentagon of water is very sensitive to the position of the hydroxyl group of Ser 6’. Electrophysiology on GLIC wild-type and Ser 6’ mutants, including single-channel recordings, confirm that the side chain hydroxyl of Ser 6’ is crucial for ion translocation. Simulations that pull a cation through the pore suggest that the ion remains hydrated during permeation and that residue 6’ actively contribute to ion translocation by reorienting its side chain when the ion is going through the pore. Generalization of these findings to the pLGIC family is proposed.