skip to main content

DOE PAGESDOE PAGES

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.
Authors:
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
Publication Date:
Grant/Contract Number:
FG02-05ER15699
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.
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
OSTI Identifier:
1454323
Alternate Identifier(s):
OSTI ID: 1454324

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., 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. 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, and Kern, Dorothee. 2018. "Dynamics of human protein kinase Aurora A linked to drug selectivity". United States. doi: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 = {2018},
month = {6}
}

Works referenced in this record:

Coot model-building tools for molecular graphics
journal, November 2004
  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925