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 we can see, at atomic resolution, a protein binding pocket for the neurotransmitter ACh. We found that the active site consists of a catalytic triad (Ser200-His440-Glu327) 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 quaternary group of the choline moiety makes close contact with the indole ring of Trp84. In order to study experimentally this interaction, in detail, we soaked into crystals of AChE a series of different inhibitors, including the competitive inhibitor edrophonium (EDR) and the transition-state analog (N,N,N-trimethylammonio) trifluoroacetophenone (TFK), and determined their 3-D structures.
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Sussman, J.L., Harel, M., Raves, M., Quinn, D., Silman, I. (1995). 3-D Structure of Acetylcholinesterase and Its Complexes with Anticholinesterase Agents. In: Pullman, A., Jortner, J., Pullman, B. (eds) Modelling of Biomolecular Structures and Mechanisms. The Jerusalem Symposia on Quantum Chemistry and Biochemistry, vol 27. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-0497-5_34
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DOI: https://doi.org/10.1007/978-94-011-0497-5_34
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