Department of Microbiology and Physiological Systems
Amino Acids, Peptides, and Proteins | Biochemistry | Biophysics | Enzymes and Coenzymes | Structural Biology
Protein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinases Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome.
protein kinases, drugs, binding, Ser/Thr-kinase Aurora A
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY 4.0 International license.
DOI of Published Version
bioRxiv 286310; doi: https://doi.org/10.1101/286310. Link to preprint on bioRxiv service.
Kern D, Pitsawong W, Brandeis University, Otten R, Agafonov RV, Zorba A, Kern N, Kutter S, Kern G, Pádua RA, Meniche X. (2018). Dynamics of human protein kinases linked to drug selectivity [preprint]. UMass Chan Medical School Faculty Publications. https://doi.org/10.1101/286310. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1536
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This work is licensed under a Creative Commons Attribution 4.0 License.