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Title: Dynamics of human protein kinase Aurora A linked to drug selectivity

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.
ORCiD logo [1] ;  [1] ; ORCiD logo [1] ;  [1] ; ORCiD logo [1] ; ORCiD logo [1] ; ORCiD logo [1] ;  [1] ; ORCiD logo [1] ;  [2] ; ORCiD logo [1]
  1. Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
  2. Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
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Journal Name: eLife Journal Volume: 7; Journal ID: ISSN 2050-084X
eLife Sciences Publications, Ltd.
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United States
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OSTI ID: 1454324