TCB Publications - Abstract
Giovanni Gonzalez-Gutierrez, Yuhang Wang, Gisela Cymes, Emad Tajkhorshid, and Claudio Grosman. Chasing the open-state structure of pentameric ligand-gated ion channels. Journal of General Physiology, 149:1119-1138, 2017. (PMC: PMC5715906)
. At the level of the transmembrane pore, the open-state models of the proton-gated pLGIC from Gloeobacter violaceus (GLIC) and the invertebrate glutamate-gated Cl- channel (GluCl) are very similar to each other, but that of the glycine receptor (GlyR) is considerably wider. Indeed, the mean distances between the axis of ion permeation and the C
atoms at the narrowest constriction of the pore (position -2') differ by 
2 in these two classes of model, a large difference when it comes to understanding the physicochemical bases of ion conduction and charge selectivity. Here, we take advantage of the extreme open-channel stabilizing effect of mutations at pore-facing position 9'. We find that the I9'A mutation slows down entry into desensitization of GLIC to the extent that macroscopic currents decay only slightly by the end of pH 4.5 solution applications to the extracellular side for several minutes. We crystallize (at pH 4.5) two variants of GLIC carrying this mutation and solve their structures to resolutions of 3.12 and 3.36 . Furthermore, we perform all-atom molecular dynamics simulations of ion permeation and picrotoxinin block, using the different open-channel structural models. On the basis of these results, we favor the notion that the open-channel structure of pLGICs from animals is much closer to that of the narrow models (of GLIC and GluCl) than it is to that of the GlyR.
