A mechanism that permits essential substances to enter our cells while at the same time removing from them harmful components also has a “down side.” This negative aspect prevents vital drugs, such as anti-cancer drugs, from achieving their designed functions, and also enables bacterial cells to develop resistance to penetration of antibiotics.
A study aimed at a fuller understanding of how this selective mechanism works -- with a view towards better controlling it through new drug designs -- is the subject of an article by Hebrew University of Jerusalem and German researchers that has been published in Proceedings of the National Academy of Sciences in the US (PNAS).
The trafficking of materials in and out of cells is controlled by a variety of proteins found in the membrane surrounding living cells, called “transporters.” It is these transporters that fulfill the important function of allowing entrance of vital compounds on the one hand and disposal of toxic compounds on the other hand.
While providing an essential survival strategy for the organism, the transporters that remove toxic compounds from the cell have been associated with the ability of the bacterial cell to develop resistance to antibiotics. In mammalian cells, transporters are responsible for some types of resistance of cancer cells to antineoplastic drugs (drugs against abnormal/cancerous growths).
Since this resistance poses serious problems in the treatment of cancers and infectious diseases, these proteins are an important target for drug design.
To progress in this pursuit, a more complete knowledge of the transporter mechanism is required, but despite many studies, this mechanism is not yet fully understood. It is, however, well established that an essential part of the mechanism stems from the ability of the transporter to change conformations. Thus, the binding site of a particular transporter is alternatively exposed either to the cell cytoplasm (interior) or to the outside environment, enabling the protein to bind its materials on one side of the cell and transport them to the other side.
The research conducted by the Hebrew University-German team focused at a model transporter expressed in the brain: VMAT (Vesicular MonoAmine Transporter). VMAT is known to transport a variety of neurotransmitters like adrenaline, dopamine and serotonin. In addition, it can also transport MPP, a neurotoxin involved in models of Parkinson’s disease.
A functional and structural link between VMAT and bacterial transporters responsible for multidrug resistance may suggest a common origin for both types of proteins. A number of studies demonstrated the significance of VMAT as a target for drug therapy in a variety of pathologic states, such as high blood pressure, hyperkinetic movement disorders and Tourette syndrome.
The research was conducted by Shimon Schuldiner, the Mathilda Marks-Kennedy Professor of Biochemistry at the Hebrew University, and his research students Dana Yaffe and Yonatan Shuster, in cooperation with a group led by Dr Lucy Forrest at the Max Planck institute in Frankfurt, Germany, and her post-doctoral associate Sebastian Radestock.A computational method was used, allowing the development of a novel model, simulating the protein’s 3D structure. The model led to a series of biochemical experiments, which in turn provided a better understanding of the transporter’s conformational changes. Specifically, the research identified interactions within the protein that mediate the conformational changes.
The researchers hope that this knowledge may, in the future, help in designing drugs for treating pathologies involving transporters similar to VMAT, including infectious and neurological diseases.
CONTACT:Jerry Barach, Hebrew University Foreign Press Liaison
Jerry Barach | Hebrew University
New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)
Reusable carbon nanotubes could be the water filter of the future, says RIT study
30.03.2017 | Rochester Institute of Technology
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