1.A.9.9.1
The bacterial pentameric Cys-loop ligand-gated ion channel (Erwinia chrysanthemi ligand-gated ion channel), ELIC. A 3.3 Å resolution structure is available (Hilf and Dutzler, 2008; Corringer et al., 2010).  X-ray analyses have identified three distinct binding sites for anaesthetics, one in the channel, one at the end of a TMS, and one in a hydrophobic pocket of the extracellular domain (Spurny et al. 2013).  Motions involving desensitization have been defined (Dellisanti et al. 2013).  Simulations indicate the similarities with and differences between the Acetylcholine receptor (Cheng et al. 2009).  This family includes members with very divergent properties (Gonzalez-Gutierrez and Grosman 2015).  Cysteamine is an agonist for ELIC (Hénault and Baenziger 2016). X-ray structures and functional measurements support a pore-blocking mechanism for the inhibitory action of short-chain alcohols which bind to the TMSs (Chen et al. 2016). GLIC (TC# 1.A.9.8.1) and ELIC may represent distinct transmembrane domain archetypes (Therien and Baenziger 2017), and both bind hopenoids at the mamalian cholesterol binding site (Barrantes and Fantini 2016).  A high-resolution structure of ELIC in a lipid-bound state has revealed a phospholipid binding site at the lower half of pore-forming transmembrane helices M1 and M4 and at a nearby site for neurosteroids, cholesterol or general anesthetics (Hénault et al. 2019). This site is shaped by an M4-helix kink and a Trp-Arg-Pro triad that is highly conserved in eukaryote GABAA/C and glycine receptors. M4 is intrinsically flexible, and M4 deletions or disruptions of the lipid-binding site accelerate desensitization, suggesting that lipid interactions shape the agonist response (Hénault et al. 2019). 1-Palmitoyl-2-oleoyl phosphatidylglycerol (POPG) stabilizes the open state of ELIC relative to the desensitized state by direct binding to specific sites (Tong et al. 2019). The nicotinic acetylcholine receptor from the Torpedo electric organ, when reconstituted in membranes formed by zwitterionic phospholipids alone, exposure to agonist fails to elicit ion-flux activity, and ELIC has a similar lipid sensitivity. Structures of ELIC in palmitoyl-oleoyl-phosphatidylcholine- (POPC-) only nanodiscs in both the unliganded (4.1-Å resolution) and agonist-bound (3.3 Å) states using single-particle cryoEM have been solved (Kumar et al. 2020). The largest differences occur at the level of loop C - at the agonist-binding sites - and the loops at the interface between the extracellular and transmembrane domains (ECD and TMD, respectively). The transmembrane pore is occluded similarly in both structures. POPC-only membranes prevent ECD-TMD coupling so that the "conformational wave" of liganded-receptor gating takes place in the ECD and the interfacial M2-M3 linker, but fails to penetrate the membrane and propagate into the TMD. The higher affinity for agonists, characteristic of the open- and desensitized-channel conformations, results from the tighter confinement of the ligand to its binding site; this limits the ligand's fluctuations, and thus delays its escape into bulk solvent (Kumar et al. 2020).