Department of Microbiology and Physiological Systems
Amino Acids, Peptides, and Proteins | Biochemistry | Biophysics | Cancer Biology | Enzymes and Coenzymes | Molecular Biology | 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-kinase 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.
E. coli, cancer biology, drug binding, enzyme kinetics, molecular biophysics, protein kinase, structural biology
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Copyright © 2018, Pitsawong et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
DOI of Published Version
Elife. 2018 Jun 14;7. pii: 36656. doi: 10.7554/eLife.36656. Link to article on publisher's site
Pitsawong W, Buosi V, Otten R, Agafonov RV, Zorba A, Kern N, Kutter S, Kern G, Padua RA, Meniche X, Kern D. (2018). Dynamics of human protein kinase Aurora A linked to drug selectivity. Open Access Publications by UMMS Authors. https://doi.org/10.7554/eLife.36656. Retrieved from https://escholarship.umassmed.edu/oapubs/3513
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This work is licensed under a Creative Commons Attribution 4.0 License.