Structural basis for ion permeation mechanism in pentameric ligand-gated ion channels

Abstract

The high-resolution crystal structure of a pentameric ligand-gated ion channel reveals that hydroxylated residues and two water pentagon rings form an ion selectivity filter, explaining ion transport across hydrophobic constriction barriers.

Allosteric and hyperekplexic mutant phenotypes investigated on an α 1 glycine receptor transmembrane structure

“…The acetylcholine binding proteins (AChBPs) homologous to the pLGIC-ECDs were first solved (4), followed by two bacterial homologs called ELIC (5) and GLIC (6). GLIC is activated by protons, and its crystallization under conditions favoring the resting (GLIC-pH7) (7) or the active (GLIC-pH4) (6,8,9) states revealed its gating mechanism. The ECDs of subunits that are loosely packed at pH 7 come closer according to a "blooming" motion following acidification, in concert with a channel opening that involves a major tilt of the M2 channel-lining helix.…”

Identifying the elusive link between amino acid sequence and charge selectivity in pentameric ligand-gated ion channels

“…27) and the invertebrate anion-selective channel α1 GluCl (PDB ID code 3RHW; resolution, 3.26 Å; ref. 23), two models that (despite some reservations) have been deemed to represent the open-channel conformation (Fig.…”

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

“…Indeed, such structural studies by X-ray crystallography and nuclear magnetic resonance spectroscopy have a crucial role in pharmaceutical research (Kim and Doyle, 2010). For example, a critical advance in our understanding of the molecular interaction of alcohol on protein comes from explorations of the bacterial pLGIC GLIC, which provided the first X-ray crystal structure of ethanol bound to a pLGIC (Sauguet et al, 2013). Emerging structural evidence indicates that ethanol occupies water-filled cavities in proteins, particularly between a-helices, and this requires hydrogen bonding with the hydroxyl group of the alcohol and usually a serine or threonine in the protein as well as weak hydrophobic interactions (Cheng et al, 2008;Harris et al, 2008;Sauguet et al, 2013).…”

“…For example, important alcohol-sensitive ion channels include potassium channels (especially GIRK), ligand-gated ion channels (including glutamate, especially NMDA), and the pentameric ligand-gated ion channels (pLGIC) (Howard et al, 2011). There has been considerable progress in defining sites of alcohol actions on several pLGIC, including g-aminobutyric acid type A (GABA A ), glycine (Gly), and nicotinic receptors (Blednov et al, 2011;Borghese and Harris, 2012;Borghese et al, 2003;McCracken et al, 2010McCracken et al, , 2013Murail et al, 2012;Sauguet et al, 2013). Importantly, genes for five of the pLGIC receptor subunits (GlyR a3, GABA A R g1, r1,2, and a2) have been linked with human alcohol dependence (Gorini et al, 2011;Han et al, 2012;Ittiwut et al, 2012;Mayfield et al, 2008;Xuei et al, 2010), but very little is known about specific roles of these subunits in alcohol actions.…”

“…For example, a critical advance in our understanding of the molecular interaction of alcohol on protein comes from explorations of the bacterial pLGIC GLIC, which provided the first X-ray crystal structure of ethanol bound to a pLGIC (Sauguet et al, 2013). Emerging structural evidence indicates that ethanol occupies water-filled cavities in proteins, particularly between a-helices, and this requires hydrogen bonding with the hydroxyl group of the alcohol and usually a serine or threonine in the protein as well as weak hydrophobic interactions (Cheng et al, 2008;Harris et al, 2008;Sauguet et al, 2013). However, crystallographic and spectroscopic methods are complex, lack dynamicity, require high protein concentrations, and can be challenging depending on the size of proteins and/or their inability to form crystals.…”