An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet
AbstractAcetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by a rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for treatment of various cholinergic deficiencies, including Alzheimer’s disease and myasthenia gravis. In a previous high throughput screening campaign, we identified the dye crystal violet (CV) as an inhibitor of AChE. Herein, we show that CV displays a significant cooperativity for binding to AChE, and the molecular basis for this observation has been investigated by X-ray crystallography. Two monomers of CV bind to residues at the entrance of the active site gorge of the enzyme. Notably, the two CV molecules have extensive intermolecular contacts with each other and with AChE. Computational analyses show that the observed CV dimer is not stable in solution, suggesting the sequential binding of two monomers. Guided by the structural analysis, we designed a set of single site substitutions, and investigated their effect on the binding of CV. Only moderate effects on the binding and the cooperativity were observed, suggesting a robustness in the interaction between CV and AChE. Taken together, we propose that the dimeric cooperative binding is due to a rare combination of chemical and structural properties of both CV and the AChE molecule itself. View Full-Text
Share & Cite This Article
Allgardsson, A.; David Andersson, C.; Akfur, C.; Worek, F.; Linusson, A.; Ekström, F. An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet. Molecules 2017, 22, 1433.
Allgardsson A, David Andersson C, Akfur C, Worek F, Linusson A, Ekström F. An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet. Molecules. 2017; 22(9):1433.Chicago/Turabian Style
Allgardsson, Anders; David Andersson, C.; Akfur, Christine; Worek, Franz; Linusson, Anna; Ekström, Fredrik. 2017. "An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet." Molecules 22, no. 9: 1433.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.