Researchers from the Institute of Cancer Research (ICR), Imperial College London and Thermo Fisher Scientific have successfully used a new imaging technique that could help advance the design of new innovative drugs for cancer.
Published in Nature Communications, the study was funded by the ICR with additional funding from Cancer Research UK, Thermo Fisher Scientific and the Medical Research Council.
Using a cutting-edge technique, cryogenic electron microscopy (cryo-EM), researchers gained better insight into how cycling-dependant kinase (CDK)-activating kinase (CAK) binds to inhibitor drug molecules.
Already showing promise as a target for cancer drugs, researchers suggest that a better understanding of CDK-CAK’s molecular composition could facilitate the structure-based design of new effective treatments.
After rapidly freezing samples to below -150°C, the team employed an improved cryo-EM workflow, which requires the specimen to be in a vacuum, and rapidly screened the samples with a less costly and more readily available instrument.
Researchers then assessed the images and identified the specimens with the highest potential to go onto the next stage, using a cold-field emission gun that provides higher-resolution images to obtain detailed views of small molecular complexes.
The team then went on to determine 16 detailed structures of the catalytic module of CAK, including both structures in its free state and those of CAK when bound to other substrates. Based on these, researchers revealed certain mechanisms of CDK7, cyclin H and MAT1 in the complex protein, which could be used in future designs of CDK7 inhibitors.
First author of the study, Victoria Cushing from the ICR, commented: “This methodological advance… has overcome a longstanding technical challenge, allowing us to achieve both high resolution and high throughput.
“We have already used it to provide detailed insight into the interactions between CAK and its inhibitors, which should support the design of next-generation therapeutics.”
Senior author, Dr Basil Greber, group leader, Structural Biology of DNA Repair Complexes group, ICR, said: “We hope that our work will enable scientists in other labs and institutions or in industry to apply this methodology to drug discovery, broadening the scope of its impact considerably.”