Next Article in Journal
Cytotoxic Activity of Origanum Vulgare L. on Hepatocellular Carcinoma cell Line HepG2 and Evaluation of its Biological Activity
Next Article in Special Issue
Why is Aged Acetylcholinesterase So Difficult to Reactivate?
Previous Article in Journal
Soluble Epoxide Hydrolase Inhibitory Activity of Components Isolated from Apios americana Medik
Previous Article in Special Issue
In Vitro Innervation as an Experimental Model to Study the Expression and Functions of Acetylcholinesterase and Agrin in Human Skeletal Muscle
Article Menu
Issue 9 (September) cover image

Export Article

Open AccessFeature PaperArticle
Molecules 2017, 22(9), 1433; doi:10.3390/molecules22091433

An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet

1
Swedish Defence Research Agency, SE-90281 Umeå, Sweden
2
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden
3
Department of Toxicological Enzymology, Bundeswehr Institute of Pharmacology and Toxicology, 80937 Munich, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 30 June 2017 / Accepted: 16 August 2017 / Published: 30 August 2017
View Full-Text   |   Download PDF [3070 KB, uploaded 30 August 2017]   |  

Abstract

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. View Full-Text
Keywords: cholinesterase; acetylcholinesterase; cooperativity; crystal violet; Hill coefficient; new modality; non-bonded bivalence cholinesterase; acetylcholinesterase; cooperativity; crystal violet; Hill coefficient; new modality; non-bonded bivalence
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top