A structural and dynamic model for the nicotinic acetylcholine receptor.

Folding of the five polypeptide subunits (alpha 2 beta gamma delta) of the nicotinic acetylcholine receptor (AChR) into a functional structural model is described. The principles used to arrange the sequences into a structure include: (1) Hydrophobicity----membrane crossing segments (2) amphipathic character----ion-carrying segments (ion channel with single group rotations) (3) molecular shape (elongated, pentagonal cylinder)----folding dimensions of exobilayer portion (4) choice of acetylcholine binding sites----specific folding of exobilayer segments (5) location of reducible disulfides (near agonist binding site)----additional specification of exobilayer arrangement (6) genetic homology----consistency of functional group choices (7) noncompetitive antagonist labeling----arrangement of bilayer helices. The AChR model is divided into three parts (a) exobilayer: 11 antiparallel beta-strands from each subunit (b) bilayer: 4 hydrophobic and 1 amphiphilic alpha-helices from each subunit and (c) cytoplasmic: one (folded) loop from each subunit. The exobilayer strands can form a closed "flower" (the "resting state") which is opened ("activated") by agonists bound perpendicular to the strands. Rearrangement of the agonists to a strand-parallel position and partial closing of the "flower" leads to a desensitized receptor. The actions of acetylcholine and succinoyl and suberoyl bis-cholines are clarified by the model. The opening and closing of the exobilayer "flower" controls access to the ion channel which is composed of the 5 amphiphilic bilayer helices. A molecular mechanism for ion flow in the channel is given. The unusual photolabeling of intrabilayer serines in alpha, beta and delta, but not in gamma-subunits near the binding site for non-competitive antagonists (NCAs) is explained. The dynamic behavior of the AChR channel and many experimental results can be interpreted in terms of the model.