Dynamics of human protein kinase Aurora A linked to drug selectivity
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-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.
- Authors:
-
[1];
[1];
[1];
[1];
[1];
[1];
[1]
- Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Publication Date:
- Research Org.:
- Brandeis Univ., Waltham, MA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health (NIH) (United States)
- OSTI Identifier:
- 1454323
- Alternate Identifier(s):
- OSTI ID: 1454324; OSTI ID: 1509825; OSTI ID: 1509835; OSTI ID: 1509836
- Grant/Contract Number:
- FG02-05ER15699; AC02-05CH11231; GM100966-01
- Resource Type:
- Published Article
- Journal Name:
- eLife
- Additional Journal Information:
- Journal Name: eLife Journal Volume: 7; Journal ID: ISSN 2050-084X
- Publisher:
- eLife Sciences Publications, Ltd.
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Pitsawong, Warintra, Buosi, Vanessa, Otten, Renee, Agafonov, Roman V., Zorba, Adelajda, Kern, Nadja, Kutter, Steffen, Kern, Gunther, Pádua, Ricardo AP, Meniche, Xavier, and Kern, Dorothee. Dynamics of human protein kinase Aurora A linked to drug selectivity. United States: N. p., 2018.
Web. doi:10.7554/eLife.36656.
Pitsawong, Warintra, Buosi, Vanessa, Otten, Renee, Agafonov, Roman V., Zorba, Adelajda, Kern, Nadja, Kutter, Steffen, Kern, Gunther, Pádua, Ricardo AP, Meniche, Xavier, & Kern, Dorothee. Dynamics of human protein kinase Aurora A linked to drug selectivity. United States. https://doi.org/10.7554/eLife.36656
Pitsawong, Warintra, Buosi, Vanessa, Otten, Renee, Agafonov, Roman V., Zorba, Adelajda, Kern, Nadja, Kutter, Steffen, Kern, Gunther, Pádua, Ricardo AP, Meniche, Xavier, and Kern, Dorothee. Thu .
"Dynamics of human protein kinase Aurora A linked to drug selectivity". United States. https://doi.org/10.7554/eLife.36656.
@article{osti_1454323,
title = {Dynamics of human protein kinase Aurora A linked to drug selectivity},
author = {Pitsawong, Warintra and Buosi, Vanessa and Otten, Renee and Agafonov, Roman V. and Zorba, Adelajda and Kern, Nadja and Kutter, Steffen and Kern, Gunther and Pádua, Ricardo AP and Meniche, Xavier and Kern, Dorothee},
abstractNote = {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.},
doi = {10.7554/eLife.36656},
journal = {eLife},
number = ,
volume = 7,
place = {United States},
year = {Thu Jun 14 00:00:00 EDT 2018},
month = {Thu Jun 14 00:00:00 EDT 2018}
}
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https://doi.org/10.7554/eLife.36656
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