Binding at five sites: effective cholera inhibitor based on cholera toxins
Cholera against cholera: a novel inhibitor prevents the cholera toxin from binding to carbohydrates found on the surface of intestinal cells. An international team of researchers has described their elegant concept in the journal Angewandte Chemie:
The protein scaffold of the inhibitor is based on an inactive cholera toxin. It is equipped with five sugar moieties to act as ligands. The inhibitor’s size and number of binding sites are both perfectly matched to the cholera toxin bearing five binding sites.
Cholera is a bacterial infectious disease that is primarily transmitted through insufficiently treated drinking water and contaminated foods. The actual pathogen is a toxin released by the bacteria; it attacks the cells of the intestine and causes life-threatening diarrhea.
Cholera toxin is a protein consisting of a toxic A unit and five nontoxic B units (CTB). Its shape resembles a blossom with five petals. The “petals” are nontoxic, but they bind to special carbohydrates—the oligosaccharide units on glycolipid GM1—on the surface of intestinal cells, initiating uptake of the toxin. Each of the five B subunits possesses a specific binding site for the special sugar motif.
In order to put a stop to the pentavalent cholera toxin, scientist at the University of Leeds (UK), Wageningen University (Netherlands), and King Abdulaziz University in Jeddah (Saudi Arabia) have now developed a pentavalent inhibitor. To make it properly fit with its counterpart they fell back on the old principle of “fighting fire with fire”: They used an inactive version of the five “petals” from CTB subunits as the protein scaffold for their inhibitor.
Led by Bruce Turnbull, the researchers induced a mutation in the GM1 binding site of the CTB subunits so that the inhibitor does not bind to the intestinal cells. In addition, a special side chain on each of the “petals” was chemically altered so that they could undergo a coupling reaction by which five ligands were then attached with flexible spacers. The ligands were chosen to be the ideal binding partners for the toxin:
the saccharide units from glycolipid GM1. The advantage of this method is that the inhibitor presents the toxin with five ligands that are in exactly the same distance apart as the five binding sites of the toxin, making it the perfect counterpart. The potency of the new pentavalent inhibitor for its target molecule is thus correspondingly high.
Although the synthesis of the sugar motif is relatively complicated, the protein scaffold can easily be produced genetically on an industrial scale, and can easily be chemically modified and the saccharides attached. The researchers hope that this synthetic technique can be used to develop further multivalent inhibitors for other protein–carbohydrate interactions.
About the Author
Dr. Bruce Turnbull is an Associate Professor in the School of Chemistry and Astbury Centre for Structural Molecular Biology at the University of Leeds. He chairs an EU COST Action network on Multivalent Glycosystems for Nanoscience and was the 2013 recipient of the Royal Society of Chemistry Carbohydrate Award.
Author: W. Bruce Turnbull, University of Leeds (United Kingdom), http://www.chem.leeds.ac.uk/People/Turnbull.html
Title: A Protein-Based Pentavalent Inhibitor of the Cholera Toxin B-Subunit
Angewandte Chemie International Edition, Permalink to the article: http://dx.doi.org/10.1002/anie.201404397
W. Bruce Turnbull | GDCh
Why do animals fight members of other species?
24.04.2015 | University of California - Los Angeles
Is a small artificially composed virus fragment the key to a Chikungunya vaccine?
24.04.2015 | Paul-Ehrlich-Institut - Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel
KAIST researchers published an article on the development of a novel technique to precisely track the 3-D positions of optically-trapped particles having complicated geometry in high speed in the April 2015 issue of Optica.
Daejeon, Republic of Korea, April 23, 2015--Optical tweezers have been used as an invaluable tool for exerting micro-scale force on microscopic particles and...
A very small and rare species of shark is swimming its way through scientific literature. But don't worry, the chances of this inches-long vertebrate biting...
Ever since computers have been small enough to be fixtures on desks and laps, their central processing has functioned something like an atomic Etch A Sketch, with electromagnetic fields pushing data bits into place to encode data.
Unfortunately, the same drawbacks and perils of the mechanical sketch board have been just as pervasive in computing: making a change often requires starting...
How is lightning initiated in thunderclouds? This is difficult to answer - how do you measure electric fields inside large, dangerously charged clouds? It was discovered, more or less by coincidence, that cosmic rays provide suitable probes to measure electric fields within thunderclouds. This surprising finding is published in Physical Review Letters on April 24th. The measurements were performed with the LOFAR radio telescope located in the Netherlands.
How is lightning initiated in thunderclouds? This is difficult to answer - how do you measure electric fields inside large, dangerously charged clouds? It was...
Max Planck researcher Buhalqem Mamtimin determines how much nitrogen oxide is released into the atmosphere from agriculturally used oases.
In order to make statements about current and future air pollution, scientists use models which simulate the Earth’s atmosphere. A lot of information such as...
23.04.2015 | Event News
23.04.2015 | Event News
13.04.2015 | Event News
24.04.2015 | Materials Sciences
24.04.2015 | Materials Sciences
24.04.2015 | Health and Medicine