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Papers In Press, published online ahead of print June 1, 2005
Institute for Molecular Bioscience, Brisbane, Queensland 4072
Corresponding Author: r.lewis{at}imb.uq.edu.au
The structures of AChBP and nAChR homology models have been used to interpret data from mutagenesis experiments at the nAChR. However, little is known about AChBP derived structures as predictive tools. Molecular surface analysis of nAChR models has revealed a conserved cleft as the likely binding site for the 4/7 a-conotoxins. Here, we used an a3ß2 model to identify ß2 subunit residues in this cleft and investigated their influence on the binding of a-conotoxins MII, PnIA and GID to the a3ß2 nAChR by two-electrode voltage-clamp analysis. While a ß2-L119Q mutation strongly reduced the affinity of all three a-conotoxins, ß2-F117A, ß2-V109A and ß2-V109G mutations selectively enhanced the binding of MII and GID. An increased activity of a-conotoxins GID and MII was also observed when the ß2-F117A mutant was combined with the a4 instead of the a3 subunit. Investigation of A10L-PnIA indicated that high affinity binding to ß2-F117A, ß2-V109A and ß2-V109G mutants was conferred by amino acids with a long side chain in position 10 (PnIA numbering). Docking simulations of 4/7 a-conotoxin binding to the a3ß2 model supported a direct interaction between mutated nAChR residues and a-conotoxin residues 6, 7 and 10. Taken together, these data provide evidence that the ß subunit contributes to a-conotoxin binding and selectivity, and demonstrate that a small cleft leading to the agonist binding site is targeted by a-conotoxins to block the nAChR.
J. Biol. Chem, 10.1074/jbc.M504229200
Submitted on April 19, 2005
Revised on June 1, 2005
Accepted on June 1, 2005
2 subunit contribution of 4/7 
-conotoxin binding to the nicotinic acetylcholine receptor
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