UMass Chan Medical School Faculty Publications

UMMS Affiliation

Department of Microbiology and Physiological Systems

Publication Date

2018-03-21

Document Type

Article Preprint

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Biophysics | Enzymes and Coenzymes | Structural Biology

Abstract

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.

Keywords

protein kinases, drugs, binding, Ser/Thr-kinase Aurora A

Rights and Permissions

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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

10.1101/286310

Source

bioRxiv 286310; doi: https://doi.org/10.1101/286310. Link to preprint on bioRxiv service.

Journal/Book/Conference Title

bioRxiv

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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