Cancer research at BESSY II: Binding Mechanisms of Therapeutic Substances Deciphered
In tumor cells, the DNA is altered in comparison to normal body cells. How such changes can be prevented or inhibited is an exciting field of research with great relevance for the development of cancer treatments. An interdisciplinary team has now analysed the possible binding mechanisms in certain therapeutic substances from the tetrazole hydrazide group using protein crystallography at BESSY II.
Certain proteins such as human histone demethylases, including the KDM4 protein, play a role in the development of tumour cells. They bind to the DNA and modify it so that the cell can become cancerous. Therapeutic substances that are able to inhibit or even reverse such changes are of particular interest.
Biochemist Prof. Dr. Udo Heinemann from the Max Delbrück Centre in Berlin-Buch is investigating such processes. In cooperation with chemists led by Prof. Dr. Andreas Link from the University of Greifswald and the team led by Dr. Manfred Weiss at the HZB, he has now investigated how and where certain therapeutic substances from the tetrazole hydrazide group dock to these protein molecules and thus inhibit their harmful effect.
KDM4 protein crystals analysed
Link initially produced variations of tetrazole hydrazide substances. For structural analysis, crystals had to be grown from KDM4 proteins - a difficult task that Dr. Piotr Malecki and Manfred Weiss had taken on at the HZB. The KDM4 protein crystals were then soaked in a specific substance before being analyzed with strong X-rays on the MX beamlines of BESSY II. A refined analysis showed not only the three-dimensional architecture of the KDM4 protein, but also exactly where the active substances had docked to the KDM4 molecule.
"This class of substances has not yet been structurally investigated," explains Manfred Weiss. And Udo Heinemann from the MDC explains: "We will now evaluate where there are opportunities to dock even stronger within the 3D structure of the KDM4. Then we might also be able to develop drugs that inhibit the KDM4 even more and thus have the potential to become a therapeutic."