Residues between positions 184 and 200 of the Torpedo acetylcholine receptor alpha 1 subunit were changed by oligonucleotide-directed mutagenesis in a recombinant fusion protein containing residues 166-211. Amino acids were substituted with residues present in the snake alpha subunit, with an alanine, or with a functionally dissimilar residue. The competitive antagonist alpha-bungarotoxin bound to the fusion protein with high apparent affinity (IC50 = 3.2 x 10(-8) M), and binding was competed by agonists and antagonists. Mutation of His-186, Tyr-189, Tyr-190, Cys-192, Cys-193, Pro-194, and Asp-195 greatly reduced or abolished alpha-bungarotoxin binding, while mutation of Tyr-198 reduced binding, indicating these residues play an important role in binding either through functional interaction with neurotoxin residues or by stabilizing the conformation of the binding site. Molecular modeling of acetylcholine receptor residues 184-200 and knowledge of both neurotoxin and receptor residues essential for binding allow analysis of possible structure-function relationships of the interaction of alpha-bungarotoxin with this region of the receptor.
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