Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine

ELIC, the pentameric ligand-gated ion channel from Erwinia chrysanthemi, is a prototype for Cys-loop receptors. Here we show that acetylcholine is a competitive antagonist for ELIC. We determine the acetylcholine–ELIC cocrystal structure to a 2.9-Å resolution and find that acetylcholine binding to an aromatic cage at the subunit interface induces a significant contraction of loop C and other structural rearrangements in the extracellular domain. The side chain of the pore-lining residue F247 reorients and the pore size consequently enlarges, but the channel remains closed. We attribute the inability of acetylcholine to activate ELIC primarily to weak cation-π and electrostatic interactions in the pocket, because an acetylcholine derivative with a simple quaternary-to-tertiary ammonium substitution activates the channel. This study presents a compelling case for understanding the structural underpinning of the functional relationship between agonism and competitive antagonism in the Cys-loop receptors, providing a new framework for developing novel therapeutic drugs

18-Crown-6 templates offset-linked pyrogallol[4]arene dimers

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Cocrystals of gabapentin with <i>C</i>-alkylresorcin[4]arenes

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Pyrogallol[4]arenes as frustrated organic solids

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Tuning underwater adhesion with cation-π interactions.

Cation-π interactions drive the self-assembly and cohesion of many biological molecules, including the adhesion proteins of several marine organisms. Although the origin of cation-π bonds in isolated pairs has been extensively studied, the energetics of cation-π-driven self-assembly in molecular films remains uncharted. Here we use nanoscale force measurements in combination with solid-state NMR spectroscopy to show that the cohesive properties of simple aromatic- and lysine-rich peptides rival those of the strong reversible intermolecular cohesion exhibited by adhesion proteins of marine mussel. In particular, we show that peptides incorporating the amino acid phenylalanine, a functional group that is conspicuously sparing in the sequences of mussel proteins, exhibit reversible adhesion interactions significantly exceeding that of analogous mussel-mimetic peptides. More broadly, we demonstrate that interfacial confinement fundamentally alters the energetics of cation-π-mediated assembly: an insight that should prove relevant for diverse areas, which range from rationalizing biological assembly to engineering peptide-based biomaterials