Researchers lay groundwork to tailor drugs for new targets in cancer therapy
In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex SF3B. Researchers led by Vlad Pena at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen have now succeeded for the first time in deciphering in atomic detail how an anti-tumor agent binds to SF3B and how it modulates its function. The new findings provide an important basis for further improving potential cancer drugs that target SF3B.
Thanks to medical advances, many types of cancer are treatable nowadays. However, a panacea for cancer is still a long way off. With some cancer types the available therapies reach their limits because either the tumor does not respond to the treatment from the onset or it becomes resistant after some time. Scientists are therefore developing strategies to tackle cancer cells at spots that have not been the target of drugs so far.
Such a clinically largely untested starting point is the protein complex SF3B. It is instrumental in the first steps of the production of proteins, the universal tools of living cells. To produce proteins, the cell first needs to bring the protein blueprints into a readable form. To this end, the blueprints are cut and recombined in a sophisticated process by a complex molecular machine, the spliceosome. SF3B, as part of the spliceosome, controls at which point the building instructions are cut. If errors occur in this step, the cell produces altered proteins which might severely disrupt cellular processes.
The idea of the researchers: They want to manipulate the function of SF3B and thus mess up the production of certain proteins in order to kill cancer cells. Scientists were already able to develop agents that bind to SF3B. These do not block SF3B completely but modulate its function, with the result that some protein blueprints are cut differently. These alterations affect cancer cells more than healthy cells.
“However, so far we know very little about how exactly these substances interact with SF3B,” says Vlad Pena, who heads the Research Group of Macromolecular Crystallography at the MPI for Biophysical Chemistry. “But this information is essential to improve the agents so that they may serve as anti-cancer drugs.”
In collaboration with the pharmaceutical company H3 Biomedicine, Pena’s team has now taken a decisive step: “For the first time, we were able to determine the three-dimensional structure of SF3B in interaction with an active substance in atomic resolution,” the structural biologist relates.
Valuable insights for drug optimization
The scientists’ results reveal in detail how the active substance pladienolide B attaches to SF3B and interferes with its function. “Pladienolide B acts like a wedge in a hinge and prevents SF3B from pivoting. This movement is necessary for SF3B to function reliably,” explains Constantin Cretu, a researcher in Pena’s team and first author of the study now published in the journal Molecular Cell.
The new insights explain previous results on similar active substances, because pladienolide B is representative of a whole class of chemical agents that vary greatly in their form but share one important feature: They all have the same chemical group in their center. “Until now, it was unclear why this chemical group is so important,” Cretu says. “Our structure of SF3B and pladienolide B now shows that precisely this group substantially contributes to the binding of the drug and related substances to SF3B.”
Moreover, the researchers’ data maps all further contacts between pladienolide B and SF3B. Based on these data one can predict where the drug can be modified and where not, Pena points out: “We hope that our insights will serve as a guide to developing novel anti-cancer agents in the future.” (fk)
Cretu C, Agrawal AA, Cook A, Will CL, Fekkes P, Smith PG, Lührmann R, Larsen N, Buonamici S, Pena V: Structural basis of splicing modulation by antitumor macrolide compounds. Molecular Cell, doi: 10.1016/j.molcel.2018.03.011 (2018).
Dr. Vlad Pena, Research Group of Macromolecular Crystallography
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Phone: +49 551 201-1046
Dr. Frederik Köpper, Press and Public Relations
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Phone: +49 551 201-1310
http://www.mpibpc.mpg.de/16014519/pr_1809 – Original press release of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany
http://www.mpibpc.mpg.de/pena – Website of the Research Group of Macromolecular Crystallography, Max Planck Institute for Biophysical Chemistry in Göttingen, Germany
Dr. Carmen Rotte | Max-Planck-Institut für biophysikalische Chemie
Structual color barcode micromotors for multiplex biosensing
21.01.2020 | Science China Press
Cyanobacteria in water and on land identified as source of methane
21.01.2020 | Forschungsverbund Berlin
For years, a new synthesis method has been developed at TU Wien (Vienna) to unlock the secrets of "strange metals". Now a breakthrough has been achieved. The results have been published in "Science".
Superconductors allow electrical current to flow without any resistance - but only below a certain critical temperature. Many materials have to be cooled down...
KIT researchers develop novel composites of DNA, silica particles, and carbon nanotubes -- Properties can be tailored to various applications
Using DNA, smallest silica particles, and carbon nanotubes, researchers of Karlsruhe Institute of Technology (KIT) developed novel programmable materials....
Styrofoam or copper - both materials have very different properties with regard to their ability to conduct heat. Scientists at the Max Planck Institute for Polymer Research (MPI-P) in Mainz and the University of Bayreuth have now jointly developed and characterized a novel, extremely thin and transparent material that has different thermal conduction properties depending on the direction. While it can conduct heat extremely well in one direction, it shows good thermal insulation in the other direction.
Thermal insulation and thermal conduction play a crucial role in our everyday lives - from computer processors, where it is important to dissipate heat as...
In order to advance the transfer of research developments from the field of quantum sensor technology into industrial applications, an application laboratory is being established at Fraunhofer IAF. This will enable interested companies and especially regional SMEs and start-ups to evaluate the innovation potential of quantum sensors for their specific requirements. Both the state of Baden-Württemberg and the Fraunhofer-Gesellschaft are supporting the four-year project with one million euros each.
The application laboratory is being set up as part of the Fraunhofer lighthouse project »QMag«, short for quantum magnetometry. In this project, researchers...
Microtubules, filamentous structures within the cell, are required for many important processes, including cell division and intracellular transport. A...
16.01.2020 | Event News
15.01.2020 | Event News
07.01.2020 | Event News
21.01.2020 | Materials Sciences
21.01.2020 | Health and Medicine
21.01.2020 | Life Sciences