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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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, Dorothee; Pitsawong, Warintra; Brandeis University; Otten, Renee; Agafonov, Roman V.; Zorba, Adelajda; Kern, Nadja; Kutter, Steffen; Kern, Gunther; Pádua, Ricardo A.P.; and Meniche, Xavier, "Dynamics of human protein kinases linked to drug selectivity" (2018). University of Massachusetts Medical School Faculty Publications. 1536.
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This work is licensed under a Creative Commons Attribution 4.0 License.