Freiburg structural biologists explain on the molecular level, how the drug atovaquone acts on the pathogen of the disease
A research team led by Prof. Dr. Carola Hunte has succeeded in describing how the antimalarial drug atovaquone binds to its target protein. The scientists used x-ray crystallography to determine the three-dimensional structure of the protein with the active substance bound.
Molecule in a pocket: The illustration shows how atovaquone binds to its target protein. Graphic: Dominic Birth, Carola Hunte
The drug combination atovaquone-proguanil (Malarone®) is a medication used worldwide for the prevention and treatment of malaria. The data and the resulting findings concerning the mode of action of atovaquone could lead to improved medications against the tropical disease.
Hunte and her team conducted the research at the Institute for Biochemistry and Molecular Biology of the Faculty of Medicine and the Centre for Biological Signalling Studies BIOSS at the University of Freiburg. The scientists published their findings in the journal Nature Communications.
Malaria is one of the most dangerous tropical diseases in the world. Anopheles mosquitoes infected with Plasmodium species – unicellular parasites – transmit the disease by biting. Atovaquone blocks a protein of the respiratory chain in the mitochondria, the power plants of the cell, thus killing off the parasites.
However, the pathogen is susceptible to mutations so that drug resistant strains are arising and spreading. The Freiburg scientists have now paved the way for the development of improved drugs by revealing the precise binding mode of atovaquone to the target protein.
They used the mitochondrial protein from cells of baker’s yeast for their analyses due to its close resemblance to the parasitic protein.
The target protein of atovaquone is the third of four enzymes of the respiratory chain in the mitochondrion. The amino acid chains of the protein form a three-dimensional pocket. The molecule of the active substance fits perfectly into this pocket, binding to amino acids at numerous positions.
These interactions are crucial for the effect atovaquone has in Plasmodium cells, ultimately leading to the death of the pathogen. The researchers conducted a protein sequence analysis, revealing that most of these docking sites are identical in the pathogen, baker’s yeast and in human cells. Atovaquone forms several bonds that are specific to the Plasmodium protein in the open area of the binding pocket.
In addition, the structural analysis revealed the molecular basis of resistances: Due to mutations that change the structure of the target protein, the substance cannot reach the designated binding mode – it doesn’t fit perfectly into the pocket anymore.
The data provides an important basis for improving antimalarial drugs. Scientists could now modify the molecular structure of atovaquone by means of structure-based drug design, ensuring that the active substance forms necessary bonds – and that the pathogen is no longer resistant to it.
Prof. Dr. Carola Hunte | University of Freiburg
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences