Journal Article

Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel

Dutzler, Raimund, Hilf, Ricarda J. C.

2009

Overview

ELIC channel structure 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. The X-ray structure of a pentameric ligand-gated ion channel from Erwinia chrysanthemi (ELIC) has recently provided structural insight into this family of ion channels at high resolution 1 . The structure shows a homo-pentameric protein with a barrel-stave architecture that defines an ion-conduction pore located on the fivefold axis of symmetry. In this structure, the wide aqueous vestibule that is encircled by the extracellular ligand-binding domains of the five subunits narrows to a discontinuous pore that spans the lipid bilayer. The pore is constricted by bulky hydrophobic residues towards the extracellular side, which probably serve as barriers that prevent the diffusion of ions. This interrupted pore architecture in ELIC thus depicts a non-conducting conformation of a pentameric ligand-gated ion channel, the thermodynamically stable state in the absence of bound ligand. As ligand binding promotes pore opening in these ion channels and the specific ligand for ELIC has not yet been identified, we have turned our attention towards a homologous protein from the cyanobacterium Gloebacter violaceus (GLIC). GLIC was shown to form proton-gated channels that are activated by a pH decrease on the extracellular side and that do not desensitize after activation 2 . Both prokaryotic proteins, ELIC and GLIC form ion channels that are selective for cations over anions with poor discrimination among monovalent cations 1 , 2 , characteristics that resemble the conduction properties of the cation-selective branch of the family that includes acetylcholine and serotonin receptors 3 , 4 . Here we present the X-ray structure of GLIC at 3.1 Å resolution. The structure reveals a conformation of the channel that is distinct from ELIC and that probably resembles the open state. In combination, both structures suggest a novel gating mechanism for pentameric ligand-gated ion channels where channel opening proceeds by a change in the tilt of the pore-forming helices.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Anions / Bacteria / Biological and medical sciences / Cations / Cell membranes. Ionic channels. Membrane pores / Cell structures and functions / Conduction / Crystalline structure / Crystallography, X-Ray / Cyanobacteria - chemistry / Cyanophyta / E coli / Erwinia chrysanthemi / Fundamental and applied biological sciences. Psychology / Gram-negative bacteria / Humanities and Social Sciences / Ion Channel Gating / Ion channels / Ion Channels - chemistry / Ion Channels - genetics / Ion Channels - metabolism / Ions / Ions - metabolism / letter / Ligands / Membrane proteins / Models, Molecular / Molecular and cellular biology / Molecular biophysics / multidisciplinary / Pectobacterium chrysanthemi - chemistry / Physiological aspects / Protein Structure, Quaternary / Protein Structure, Tertiary / Protein Subunits - chemistry / Protein Subunits - metabolism / Proteins / Protons / Science / Science (multidisciplinary) / Structure / Structure in molecular biology / Studies