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

M. Stornaiuolo, G.E. de Kloe, P. Rucktooa, A. Fish, R. van Elk, E.S. Edink, D. Bertrand, A.B. Smit, I.J.P. de Esch, T.K. Sixma

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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. © 2013 Macmillan Publishers Limited. All rights reserved.
Original languageEnglish
Article number1875
Pages (from-to)1875
JournalNature Communications
Volume4
Early online date21 May 2013
DOIs
Publication statusPublished - 2013

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acetylcholine
Acetylcholine
Carrier Proteins
assembly
Binding Sites
Ligands
proteins
ligands
Cysteine Loop Ligand-Gated Ion Channel Receptors
Molecules
Drug Design
Nicotinic Receptors
Ion Channels
Plasticity
Water
plastic properties
molecules
Pharmaceutical Preparations
drugs
adjusting

Cite this

Stornaiuolo, M., de Kloe, G. E., Rucktooa, P., Fish, A., van Elk, R., Edink, E. S., ... Sixma, T. K. (2013). Assembly of a π–π stack of ligands in the binding site of an acetylcholine-binding protein. Nature Communications, 4, 1875. [1875]. https://doi.org/10.1038/ncomms2900
Stornaiuolo, M. ; de Kloe, G.E. ; Rucktooa, P. ; Fish, A. ; van Elk, R. ; Edink, E.S. ; Bertrand, D. ; Smit, A.B. ; de Esch, I.J.P. ; Sixma, T.K. / Assembly of a π–π stack of ligands in the binding site of an acetylcholine-binding protein. In: Nature Communications. 2013 ; Vol. 4. pp. 1875.
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Stornaiuolo, M, de Kloe, GE, Rucktooa, P, Fish, A, van Elk, R, Edink, ES, Bertrand, D, Smit, AB, de Esch, IJP & Sixma, TK 2013, 'Assembly of a π–π stack of ligands in the binding site of an acetylcholine-binding protein' Nature Communications, vol. 4, 1875, pp. 1875. https://doi.org/10.1038/ncomms2900

Assembly of a π–π stack of ligands in the binding site of an acetylcholine-binding protein. / Stornaiuolo, M.; de Kloe, G.E.; Rucktooa, P.; Fish, A.; van Elk, R.; Edink, E.S.; Bertrand, D.; Smit, A.B.; de Esch, I.J.P.; Sixma, T.K.

In: Nature Communications, Vol. 4, 1875, 2013, p. 1875.

Research output: Contribution to JournalArticleAcademicpeer-review

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AB - 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. © 2013 Macmillan Publishers Limited. All rights reserved.

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