Biology Department Seminar

The role of acetylcholinesterase (AChE) is to stop the nervous influx at cholinergic synapses by breaking down the neurotransmitter acetylcholine. AChE is a fast acting enzyme with a buried active site, thus the challenge has been to “watch” how the enzyme works. My investigations primarily aimed at performing kinetic X-ray crystallography (KX) on the enzyme, the goal of KX being to trap intermediate states of an enzymatic reaction. I successfully trapped such an intermediate state: AChE in the process of being inhibited by the nerve agent soman. I also solved several crystal structures of AChE in complex with potential anti-Alzheimer drugs and with a mycotoxin inhibitor called aflatoxin. In the case of aflatoxin, careful crystallographic control experiments allowed assessing the influence of both the solvent and the crystal packing on structural changes. One of the structural changes was the opening of the AChE 'backdoor', postulated many years ago on the basis of MD simulations, and which could explain the fast trafficking of products and substrates in the enzyme. In parallel, I conducted spectroscopic experiments on AChE/aflatoxin complexes and developed a method that could allow studying the slow dynamics of proteins, based on the phosphorescence properties of suitable bound ligands. These structural and dynamical insights will help design new anti-Alzheimer drugs or antidotes against nerve agents that target AChE.