Dynamics of human protein kinase Aurora A linked to drug selectivity

Pitsawong, Warintra; Buosi, Vanessa; Otten, Renee; Agafonov, Roman V.; Zorba, Adelajda; Kern, Nadja; Kutter, Steffen; Kern, Gunther; Pádua, Ricardo AP; Meniche, Xavier; Kern, Dorothee

doi:10.7554/eLife.36656

Dynamics of human protein kinase Aurora A linked to drug selectivity

Journal Article · Thu Jun 14 00:00:00 EDT 2018 · eLife

DOI:https://doi.org/10.7554/eLife.36656· OSTI ID:1454323

^[1]; Buosi, Vanessa ^[1]; ^[1]; Agafonov, Roman V. ^[1]; ^[1]; ^[1]; ^[1]; Kern, Gunther ^[1]; ^[1]; Meniche, Xavier ^[2]; ^[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

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.

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Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: FG02-05ER15699

OSTI ID:: 1454323

Alternate ID(s):: OSTI ID: 1509825
OSTI ID: 1509835
OSTI ID: 1509836
OSTI ID: 1454324

Journal Information:: eLife, Journal Name: eLife Vol. 7; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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Dynamics of human protein kinase Aurora A linked to drug selectivity

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Dynamics of human protein kinase Aurora A linked to drug selectivity

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