Department of Structural Biology and Israel Structural Proteomics Center Weizmann Institute of Science
Joel Sussman is an outstanding structural biologist, primarily famous for his work on acetylcholine esterase, an enzyme intimately involved in acute neurotoxicity caused by nerve agents and pesticides. Among other distinctions, he is the Morton and Gladys Pickman Professor of Structural Biology at the Weizmann Institute, director of the Israel Structural Proteomics Center, and also former director of the Protein Data Bank (1994-1999).
The synaptic enzyme acetylcholinesterase (AChE) terminates transmission at cholinergic synapses by very rapidly hydrolysing acetylcholine. Examination of the 3D structure of AChE shows that the active site is located at the bottom of a deep and narrow gorge, lined largely by aromatic residues, with its peripheral anionic site located at the top, near the entrance to of the gorge. AChE is the target of nerve agents, insecticides and therapeutic drugs, in particular the first generation of anti-Alzheimer drugs. 3D structures of AChE have been determined for the Torpedo, Electrophorus, mouse, Drosophila and human enzymes. More than a hundred crystal structures of AChEs, and inhibitor complexes have been determined. Although the 3D structure of the enzyme is remarkably conserved, subtle structural differences are seen to occur upon the binding of certain inhibitors. These changes are well correlated with molecular dynamics data, and appear to be of functional significance.
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