Abstract
α‐Conotoxins, from cone snails, and α‐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 α‐neurotoxins to be docked onto the α7 nAChR. To investigate if α‐conotoxins interact with the nAChR in a similar manner, we built homology models of human α7 and α3__β__2 nAChRs, and performed docking simulations of α‐conotoxins ImI, PnIB, PnIA and MII using the program GOLD. Docking revealed that α‐conotoxins have a different mode of interaction compared with α‐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 __β__9/__β__10 hairpin of the (+)α7 nAChR subunit. Interestingly, PnIB, PnIA and MII were found to bind in a similar location on α7 or α3__β__2 receptors mostly through hydrophobic interactions, while ImI bound further from the ACh binding pocket, mostly through electrostatic interactions. These findings, which distinguish α‐conotoxin and α‐neurotoxin binding modes, have implications for the rational design of selective nAChR antagonists. Copyright © 2004 John Wiley & Sons, Ltd.