Determination of alpha-conotoxin binding modes on neuronal nicotinic acetylcholine receptors

Dutertre, Sébastien, Nicke, Annette, Tyndall, Joel D. A. and Lewis, Richard J. (2004) Determination of alpha-conotoxin binding modes on neuronal nicotinic acetylcholine receptors. Journal of Molecular Recognition, 17 4: 339-347. doi:10.1002/jmr.683

Author Dutertre, Sébastien
Nicke, Annette
Tyndall, Joel D. A.
Lewis, Richard J.
Title Determination of alpha-conotoxin binding modes on neuronal nicotinic acetylcholine receptors
Journal name Journal of Molecular Recognition   Check publisher's open access policy
ISSN 0952-3499
Publication date 2004-01-01
Sub-type Article (original research)
DOI 10.1002/jmr.683
Volume 17
Issue 4
Start page 339
End page 347
Total pages 9
Place of publication Chichester
Publisher John Wiley & Sons Ltd
Language eng
Subject C1
320702 Central Nervous System
730104 Nervous system and disorders
Abstract alpha-Conotoxins, from cone snails, and alpha-neurotoxins, from snakes, are competitive inhibitors of nicotinic acetylcholine receptors (nAChRs) that have overlapping binding sites in the ACh binding pocket. These disulphide-rich peptides are used extensively as tools to localize and pharmacologically characterize specific nAChRs subtypes. Recently, a homology model based on the high-resolution structure of an ACh binding protein (AChBP) allowed the three-fingered alpha-neurotoxins to be docked onto the alpha7 nAChR. To investigate if alpha-conotoxins interact with the nAChR in a similar manner, we built homology models of human alpha7 and alpha3beta2 nAChRs, and performed docking simulations of alpha-conotoxins ImI, PnIB, PnIA and MII using the program GOLD. Docking revealed that alpha-conotoxins have a different mode of interaction compared with alpha-neurotoxins, with surprisingly few nAChR residues in common between their overlapping binding sites. These docking experiments show that Imi and PnIB bind to the ACh binding pocket via a small cavity located above the beta9/beta10 hairpin of the (+)alpha7 nAChR subunit. Interestingly, PnIB, PnIA and MII were found to bind in a similar location on alpha7 or alpha3beta2 receptors mostly through hydrophobic interactions, while ImI bound further from the ACh binding pocket, mostly through electrostatic interactions. These findings, which distinguish alpha-conotoxin and alpha-neurotoxin binding modes, have implications for the rational design of selective nAChR antagonists. Copyright (C) 2004 John Wiley Sons, Ltd.
Keyword Biochemistry & Molecular Biology
Neuronal Nicotinic Acetylcholine Receptors
Homology Modeling
Pairwise Interactions
Q-Index Code C1

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Created: Wed, 15 Aug 2007, 15:10:16 EST