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An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2017 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 9, article id 1433Article in journal (Refereed) Published
Abstract [en]

Acetylcholinesterase (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.

Place, publisher, year, edition, pages
MDPI AG , 2017. Vol. 22, no 9, article id 1433
Keyword [en]
cholinesterase, acetylcholinesterase, cooperativity, crystal violet, Hill coefficient, new modality, non-bonded bivalence
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-140654DOI: 10.3390/molecules22091433ISI: 000411499400040OAI: oai:DiVA.org:umu-140654DiVA, id: diva2:1149835
Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2018-01-13Bibliographically approved

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