Finding new therapeutics to benefit patients suffering from disease is of utmost importance. However, many diseases, ranging from viral infections to cancer, pose great challenges to the drug discovery process. One avenue towards overcoming these hurdles is structure-based drug design, a process in which three-dimensional structures of biomolecules or molecular complexes serve to guide drug discovery. With recent progress in cryo-electron microscopy, new targets that were previously intractable are now becoming amenable to structure-based drug design approaches.
Our cover image for the February 16 issue of Biophysical Journal shows computational renderings of the cryo-electron microscopy structure of the human CDK-activating kinase in complex with ICEC0942, a small molecule that is undergoing clinical trials for cancer therapy. The structural work was front and center in our study, and we decided our cover illustration should show the molecular model prominently. We placed three molecules of declining size and opacity on our cover to provide an arc-like visual flow across the image and to provide a sense of depth. The frontmost molecule, the largest, presents the active site region of the kinase CDK7 with the bound inhibitor shown in purple to highlight the focus of our study. Being able to observe how ICEC0942 binds to its target may provide avenues towards designing next-generation compounds with desirable properties, such as being more specific for CDK7. While the frontmost molecule focuses on the inhibitor binding site, the other two show all important components of the human CDK-activating kinase—its three subunits CDK7, cyclin H, and MAT1 as well as the important regulatory T-loop on CDK7, which assumes its active conformation in our complex. This serves as a reminder that even though we may want to zoom in on the binding site of our molecules of interest as much as possible, it is important to study biomolecules in the context of their native complexes to ensure that we capture their functionally relevant states.
For more information on our work, readers may visit the websites of the Nogales and Greber laboratories at http://cryoem.berkeley.edu and http://www.greberlab.org.
- Basil J. Greber, Jonathan Remis, Simak Ali, Eva Nogales