3-D Structure of Acetylcholinesterase and Complexes of it with Anticholinesterase Agents

Abstract

The principal biological role of acetylcholinesterase (AChE) is termination of impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter acetylcholine (ACh). Based on our recent X-ray crystallographic structure determination of AChE from Torpedo californica ([Sussman et al. (1991)]), we can see, for the first time, at atomic resolution, a protein binding pocket of the neurotransmitter ACh. We found that the active site consists of a catalytic triad (S200-H440-E327) which lies close to the bottom of a deep and narrow gorge, that is lined with the rings of 14 aromatic amino acid residues. Despite the complexity of this array of aromatic rings, we suggested, on the basis of modelling which involved docking of the ACh molecule in an all-trans conformation, that the quatemary group of the choline moiety makes close contact with the indole ring of WM. A variety of AChE inhibitors have been synthesized and characterized pharmacologically, due to the fact that symptomatic treatment of diseases, whose etiology involves depletion of ACh levels, can be achieved by controlled inhibition of AChE. Inhibition of the catalytic activity of AChE with anticholinesterase agents is thus of therapeutic importance in countering the effects of diseases such as glaucoma and myasthenia gravis, and the possible management of Alzheimer’s disease. In order to study the interactions of AChE with these agents, in detail, we have soaked into crystals of AChE a series of different inhibitors, and recently determined the 3-D structure of AChE:Edrophonium and AChE:Tacrine. Edrophonium is a drug used in diagnosis of myasthenia gravis, it contains a quatemary ammonium group and acts at neuromuscular junctions. Tacrine is an AChE inhibitor lacking a quatemary ammonium group; hence it can penetrate the blood brain barrier and act on the central nervous system and is currently being evaluated as a drug for the management of Alzheimer’s disease. The crystal structures of both 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.