X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation

Pentameric ligand-gated ion channels from the Cys- loop family mediate fast chemo-electrical transduction(1-3), but the mechanisms of ion permeation and gating of these membrane proteins remain elusive. Here we present the X- ray structure at 2.9 angstrom resolution of the bacterial Gloeobacter violaceus pentameric ligand- gated ion channel homologue(4) ( GLIC) at pH 4.6 in an apparently open conformation. This cationic channel is known to be permanently activated by protons(5). The structure is arranged as a funnel- shaped transmembrane pore widely open on the outer side and lined by hydrophobic residues. On the inner side, a 5 angstrom constriction matches with rings of hydrophilic residues that are likely to contribute to the ionic selectivity(6-9). Structural comparison with ELIC, a bacterial homologue from Erwinia chrysanthemi solved in a presumed closed conformation(10), shows a wider pore where the narrow hydrophobic constriction found in ELIC is removed. Comparative analysis of GLIC and ELIC reveals, in concert, a rotation of each extracellular beta-sandwich domain as a rigid body, interface rearrangements, and a reorganization of the transmembrane domain, involving a tilt of the M2 and M3 alpha-helices away from the pore axis. These data are consistent with a model of pore opening based on both quaternary twist and tertiary deformation.