We constructed a three-dimensional model of the amino-terminal extracellular domain of three major types of nicotinic acetylcholine receptor, (alpha7)5, (alpha4)2(beta2)3, and (alpha1)2beta1gammadelta, on the basis of the recent x-ray structure determination of the molluscan acetylcholine-binding protein. Comparative analysis of the three models reveals that the agonist-binding pocket is much more conserved than the overall structure. Differences exist, however, in the side chains of several residues. In particular, a phenylalanine residue, present in beta2 but not in alpha7, is proposed to contribute to the high affinity for agonists in receptors containing the beta2 subunit. The semiautomatic docking of agonists in the ligand-binding pocket of (alpha7)5 led to positions consistent with labeling and mutagenesis experiments. Accordingly, the quaternary ammonium head group of nicotine makes a pi-cation interaction with W148 (alpha7 numbering), whereas the pyridine ring is close to both the cysteine pair 189-190 and the complementary component of the binding site. The intrinsic affinities inferred from docking give a rank order epibatidine > nicotine > acetylcholine, in agreement with experimental values. Finally, our models offer a structural basis for potentiation by external Ca2+.