Elephants in the Dark: Insights and Incongruities in Pentameric Ligand-gated Ion Channel Models

[Display omitted] •Pentameric ligand-gated ion channel structures now approach 250 data-bank entries.•GLIC, nicotinic receptors, and glycine receptors highlight common structural themes.•Functional states, gating mechanisms, ligand/lipid interactions remain challenging.•Like an elephant in darkness, comprehensive models require multiple sources of data. The superfamily of pentameric ligand-gated ion channels (pLGICs) comprises key players in electrochemical signal transduction across evolution, including historic model systems for receptor allostery and targets for drug development. Accordingly, structural studies of these channels have steadily increased, and now approach 250 depositions in the protein data bank. This review contextualizes currently available structures in the pLGIC family, focusing on morphology, ligand binding, and gating in three model subfamilies: the prokaryotic channel GLIC, the cation-selective nicotinic acetylcholine receptor, and the anion-selective glycine receptor. Common themes include the challenging process of capturing and annotating channels in distinct functional states; partially conserved gating mechanisms, including remodeling at the extracellular/transmembrane-domain interface; and diversity beyond the protein level, arising from posttranslational modifications, ligands, lipids, and signaling partners. Interpreting pLGIC structures can be compared to describing an elephant in the dark, relying on touch alone to comprehend the many parts of a monumental beast: each structure represents a snapshot in time under specific experimental conditions, which must be integrated with further structure, function, and simulations data to build a comprehensive model, and understand how one channel may fundamentally differ from another.