3-DIMENSIONAL STRUCTURE OF ACETYLCHOLINESTERASE AND OF ITS COMPLEXES WITH ANTICHOLINESTERASE DRUGS

Based on our recent X-ray crystallographic determination of the struct ure of acetylcholinesterase (AChE) from Torpedo californica, we can se e for the first time, at atomic resolution, a protein binding pocket f or the neurotransmitter, acetylcholine. It was found that the active s ite consists of a catalytic triad (S200-H440-E327) which lies close to the bottom of a deep and narrow gorge, which is lined with the rings of 14 aromatic amino acid residues. Despite the complexity of this arr ay of aromatic rings, we suggested, on the basis of modelling which in volved docking of the acetylcholine (ACh) molecule in an all-trans con figuration, that the quaternary group of the choline moiety makes clos e contact with the indole ring of W84. In order to study the interacti on of AChE with anticholinesterase drugs at the structural level, we h ave incorporated into the acetylcholinesterase crystals several differ ent inhibitors, and have recently determined the 3-D structure of AChE :edrophonium and AChE:tacrine complexes. The crystal structures of bot h of these complexes are in good agreement with our model building of the ACh bound in the active site of AChE and indicate the interactions of these two drugs with the enzyme.