Assembly of a π–π stack of ligands in the binding site of an acetylcholine-binding protein

• Published in: Nature communications Vol. 4; no. 1; pp. 1875 - 11
• Main Authors: Stornaiuolo, Mariano, De Kloe, Gerdien E., Rucktooa, Prakash, Fish, Alexander, van Elk, René, Edink, Ewald S., Bertrand, Daniel, Smit, August B., de Esch, Iwan J. P., Sixma, Titia K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.05.2013; Nature Publishing Group; Nature Pub. Group
• Subjects: 639/638/309/2144; 639/638/92/613; Acetylcholine - metabolism; Acetylcholine receptors (nicotinic); Acetylcholine-binding protein; Acridine Orange - metabolism; Animals; Assembly; Binding Sites; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Crystallography, X-Ray; Drug development; Electrons; Fluorescence; Homology; Humanities and Social Sciences; Ion channels; Ligands; Models, Molecular; multidisciplinary; Protein Binding; Proteins; Receptors; Science
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2900

Acetylcholine-binding protein is a water-soluble homologue of the extracellular ligand-binding domain of cys-loop receptors. It is used as a structurally accessible prototype for studying ligand binding to these pharmaceutically important pentameric ion channels, in particular to nicotinic acetylcholine receptors, due to conserved binding site residues present at the interface between two subunits. Here we report that an aromatic conjugated small molecule binds acetylcholine-binding protein in an ordered π–π stack of three identical molecules per binding site, two parallel and one antiparallel. Acetylcholine-binding protein stabilizes the assembly of the stack by aromatic contacts. Thanks to the plasticity of its ligand-binding site, acetylcholine-binding protein can accommodate the formation of aromatic stacks of different size by simple loop repositioning and minimal adjustment of the interactions. This type of supramolecular binding provides a novel paradigm in drug design. AChBP is used as a structurally accessible prototype for studying ligand binding to nicotinic acetylcholine receptors. Stornaiuolo et al . report that a small molecule binds AChBP in an ordered p–p stack of three molecules per binding site, which may lead to new approaches in drug design.