Pioneering potential targets for anti-cancer drugs

In order to maintain rapid growth, cancer cells must absorb nutrients faster than healthy cells. The human glutamine transporter ASCT2 allows glutamine, an amino acid, to enter cells and is upregulated in many types of cancer cells, which need more glutamine. This is a potential target for new anticancer drugs. Researchers at the University of Groningen have now unraveled a structure of human ASCT2 that provides unprecedented insight into how this protein works and could help drug development. The results were published in Nature Communications July 31, 2019.

This work allowed the researchers to solve a long-lasting riddle. It was known that these carriers functioned as a lift, where glutamine is absorbed by the protein, and then transported a long distance across the cell membrane, from the outside to the inside of the cell. Although we know how the substrate enters the elevator outside, the content of the interior remains enigmatic. This study now shows for the first time how the transported glutamine is released into the cytoplasm of the cell. The release mechanism is surprisingly similar to its capture mechanism located outside the cell. The same door – a.k.a elevator door – uses on either side of the membrane. "We therefore qualified the transport mechanism as" lift to a door ", which distinguishes it from the most commonly observed mechanisms that use two different doors for entry and release," said Dr. Dirk Slotboom.

Dr Cristina Paulino said: "This observation is of fundamental interest, but also has potential implications for drug design.An important consequence of the elevator mechanism at a door is that important protein movements take place in the cell membrane during transport. " Therefore, lipids (the constituent molecules of the cell membrane) are likely to affect the functioning of the protein. In fact, the authors have found many lipid-like molecules badociated with the protein, where they occupy cavities on the surface. Since these cavities need to be left vacant to allow the elevator to move, small molecules that bind closely to these sites could have properties similar to those of a drug.

Future studies will focus on the research and characterization of these molecules, which could lead to the development of new anti-cancer drugs in the near future.