Journal of Neuroscience Research vol:16 issue:1 pages:51-73
A detailed model for the acetylcholine binding site on the nicotinic acetylcholine receptor is proposed. It is derived from assumptions based on existing biochemical, structural, and pharmacological data, combined with molecular modeling and principles of protein evolution and architecture. Acetylcholine is proposed to fit into a pocket on one face of an antiparallel beta-pleated sheet formed by residues 128-142 on the alpha-subunit. This sheet is flexible yet stable, in part because of a double cystine bridge at its end. Asp138, Thr133, and Gln140 provide a ring of negative charges around the quaternary ammonium group of acetylcholine, Ile131 and alkane segments of the other residues in the binding site provide hydrophobic interactions, and Gln140 provides a hydrogen bond for acetylcholine's carbonyl group; Glu129 would form part of the second anionic subsite for the bis-quaternary ammonium compounds and curares. The model is compatible with the available evidence pertaining to the binding site and with structure-activity relationship studies. It is precise and detailed, thereby making clear predictions, which are directly testable by affinity labeling and site-directed mutagenesis. It should prove useful in the design of such experiments.