Dynamics of human protein kinase Aurora A linked to drug selectivity
- Howard Hughes Medical Institute, Brandeis University, United States
- 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.
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Structure of apo, dephosphorylated Aurora A (122-403) in an active conformationPublicly available at RCSB Protein Data Bank (accession no: 6CPE).
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Structure of dephosphorylated Aurora A (122-403) bound to AMPPCP in an active conformationPublicly available at RCSB Protein Data Bank (accession no: 6CPF).
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Structure of dephosphorylated Aurora A (122-403) in complex with inhibiting monobody and AT9283 in an inactive conformationPublicly available at RCSB Protein Data Bank (accession no: 6CPG).
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Structure of dephosphorylated Aurora A (122-403) bound to AMPPCPPublicly available at RCSB Protein Data Bank (accession no: 4C3R).
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CRYSTAL STRUCTURE OF AURORA-2, AN ONCOGENIC SERINE-THREONINE KINASEPublicly available at RCSB Protein Data Bank (accession no: 1MUO).
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Structure of Human Aurora-A 122-403 phosphorylated on Thr287, Thr288Publicly available at RCSB Protein Data Bank (accession no: 1OL7).
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Structure determination of Aurora Kinase in complex with inhibitorPublicly available at RCSB Protein Data Bank (accession no: 2W1G).
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Structure of Aurora-2 in complex with PHA-739358Publicly available at RCSB Protein Data Bank (accession no: 2J50).
Article and author information
Author details
Warintra Pitsawong
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.
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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