Dynamics of human protein kinase Aurora A linked to drug selectivity

  1. Warintra Pitsawong
  2. Vanessa Buosi
  3. Renee Otten
  4. Roman V Agafonov
  5. Adelajda Zorba
  6. Nadja Kern
  7. Steffen Kutter
  8. Gunther Kern
  9. Ricardo AP Pádua
  10. Xavier Meniche
  11. Dorothee Kern  Is a corresponding author
  1. Howard Hughes Medical Institute, Brandeis University, United States
  2. University of Massachusetts Medical School, United States

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.

Data availability

Diffraction data have been deposited in PDB under the accession codes 6CPE, 6CPF, 6CPG.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Warintra Pitsawong

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5438-1783
  2. Vanessa Buosi

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Renee Otten

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7342-6131
  4. Roman V Agafonov

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Adelajda Zorba

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4452-8419
  6. Nadja Kern

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Steffen Kutter

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gunther Kern

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ricardo AP Pádua

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Xavier Meniche

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Dorothee Kern

    Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
    For correspondence
    dkern@brandeis.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7631-8328

Funding

Howard Hughes Medical Institute

  • Dorothee Kern

National Institutes of Health (GM100966-01)

  • Dorothee Kern

U.S. Department of Energy (DE-FG02-05ER15699)

  • Dorothee Kern

Damon Runyon Cancer Research Foundation (DRG-2114-12)

  • Renee Otten

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Philip A Cole, Harvard Medical School, United States

Version history

  1. Received: March 14, 2018
  2. Accepted: June 12, 2018
  3. Accepted Manuscript published: June 14, 2018 (version 1)
  4. Version of Record published: July 20, 2018 (version 2)

Copyright

© 2018, Pitsawong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Warintra Pitsawong
  2. Vanessa Buosi
  3. Renee Otten
  4. Roman V Agafonov
  5. Adelajda Zorba
  6. Nadja Kern
  7. Steffen Kutter
  8. Gunther Kern
  9. Ricardo AP Pádua
  10. Xavier Meniche
  11. Dorothee Kern
(2018)
Dynamics of human protein kinase Aurora A linked to drug selectivity
eLife 7:e36656.
https://doi.org/10.7554/eLife.36656

Share this article

https://doi.org/10.7554/eLife.36656

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