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Comparison of the Binding of Reversible Inhibitors to Human Butyrylcholinesterase and Acetylcholinesterase: A Crystallographic, Kinetic and Calorimetric Study

1
Departments of Neuroscience and Pharmacology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
2
Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91220 Brétigny-sur-Orge, France
3
Department of Diagnostic Radiology, Dalhousie University, Halifax, NS B3H 4R2, Canada
4
Department of Medical Neuroscience, Dalhousie University, Halifax, NS B3H 4R2, Canada
5
Department of Chemistry, Mount Saint Vincent University, Halifax, NS B3M 2J6, Canada
6
Department of Medicine (Neurology and Geriatric Medicine), Dalhousie University, Halifax, NS B3H 4R2, Canada
*
Author to whom correspondence should be addressed.
Deceased October 2016.
Molecules 2017, 22(12), 2098; https://doi.org/10.3390/molecules22122098
Received: 26 October 2017 / Revised: 26 November 2017 / Accepted: 27 November 2017 / Published: 29 November 2017
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze the neurotransmitter acetylcholine and, thereby, function as coregulators of cholinergic neurotransmission. Although closely related, these enzymes display very different substrate specificities that only partially overlap. This disparity is largely due to differences in the number of aromatic residues lining the active site gorge, which leads to large differences in the shape of the gorge and potentially to distinct interactions with an individual ligand. Considerable structural information is available for the binding of a wide diversity of ligands to AChE. In contrast, structural data on the binding of reversible ligands to BChE are lacking. In a recent effort, an inhibitor competition approach was used to probe the overlap of ligand binding sites in BChE. Here, we extend this study by solving the crystal structures of human BChE in complex with five reversible ligands, namely, decamethonium, thioflavin T, propidium, huprine, and ethopropazine. We compare these structures to equivalent AChE complexes when available in the protein data bank and supplement this comparison with kinetic data and observations from isothermal titration calorimetry. This new information now allows us to define the binding mode of various ligand families and will be of importance in designing specific reversible ligands of BChE that behave as inhibitors or reactivators. View Full-Text
Keywords: acetylcholinesterase; butyrylcholinesterase; crystal structure; kinetics; isothermal titration calorimetry acetylcholinesterase; butyrylcholinesterase; crystal structure; kinetics; isothermal titration calorimetry
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MDPI and ACS Style

Rosenberry, T.L.; Brazzolotto, X.; Macdonald, I.R.; Wandhammer, M.; Trovaslet-Leroy, M.; Darvesh, S.; Nachon, F. Comparison of the Binding of Reversible Inhibitors to Human Butyrylcholinesterase and Acetylcholinesterase: A Crystallographic, Kinetic and Calorimetric Study. Molecules 2017, 22, 2098.

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