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

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Abstract
Recently, the first crystal structure of a pentameric ligand-gated ion channel known as GLIC was published, which represented a closed state of the channel. Two papers in this issue report the crystal structures of the presumptive open states of a related channel — ELIC —and show significant tilting of the M2 and M3 α-helices from the closed state. Recently, the first crystal structure of a pentameric ligand-gated ion channel known as GLIC was published, which represented a closed state of the channel. In two papers in this issue, presumptive open states of a related channel — ELIC — have been crystallized and show significant tilting of the M2 and M3 α-helices from the closed state. Pentameric ligand-gated ion channels from the Cys-loop family mediate fast chemo-electrical transduction1,2,3, but the mechanisms of ion permeation and gating of these membrane proteins remain elusive. Here we present the X-ray structure at 2.9 Å resolution of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel homologue4 (GLIC) at pH 4.6 in an apparently open conformation. This cationic channel is known to be permanently activated by protons5. 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 Å constriction matches with rings of hydrophilic residues that are likely to contribute to the ionic selectivity6,7,8,9. Structural comparison with ELIC, a bacterial homologue from Erwinia chrysanthemi solved in a presumed closed conformation10, 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 β-sandwich domain as a rigid body, interface rearrangements, and a reorganization of the transmembrane domain, involving a tilt of the M2 and M3 α-helices away from the pore axis. These data are consistent with a model of pore opening based on both quaternary twist and tertiary deformation.

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