THE NICOTINIC CHOLINERGIC RECEPTOR - A THEORETICAL-MODEL

Based on published affinity-labelling and mutagenesis experiments desc ribing the effect of changes in specific amino acids in molecular biol ogical studies on the nicotinic acetylcholinergic receptor (nAChR), we have identified 12 amino acids which are important in functioning at the nicotinic cholinergic receptor, The work presented here provides a n atomistic model of this important receptor based on our molecular mo delling studies, We found five of these amino acids (TRP86, ASP89, TYR 93, ASP138, and THR191) to be associated with the cationic end of acet ylcholine (ACh), which is electron-deficient, Three other amino acids (ARG209, TYR190, and TYR198) are associated with the ester end, where an enhanced electron density is present, After hydrogen bonding betwee n the two oxygen atoms at the ester end, and two of the guanidinium hy drogen atoms in ARG209, ASP200 hydrogen bonds to the other two hydroge n atoms of the guanidinium group, thus forming a pseudo-ring, Two arom atic amino acids (TRP149 and TYR151) then enhance the binding at the p seudo-ring through additional hydrogen bonding and charge-transfer com plexation, with THR150 functioning to further stabilize this evolving charge-transfer complex, We postulate that this latter process allows the ion channel to twist, thus opening it, From the published amino ac id sequence in the polypeptides at the 5HT-3, GABA, and glycine recept ors (Maricq et al.: Science 254:432-437, 1991), we also speculate on w hich amino acids are involved in these three receptors. (C) 1996 Wiley -Liss, Inc.