期刊
CHEMISTRY & BIOLOGY
卷 21, 期 5, 页码 628-635出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2014.02.016
关键词
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资金
- National Institutes of Health [R01 GM086858]
- Alfred P. Sloan Foundation
- Camille and Henry Dreyfus Foundation
- American Heart Association
- DOE Office of Biological and Environmental Research
- National Institute of General Medical Sciences (NIGMS), National Institutes of Health (NIH) [P41GM103393]
Most potent protein kinase inhibitors act by competing with ATP to block the phosphotransferase activity of their targets. However, emerging evidence demonstrates that ATP-competitive inhibitors can affect kinase interactions and functions in ways beyond blocking catalytic activity. Here, we show that stabilizing alternative ATP-binding site conformations of the mitogen-activated protein kinases (MAPKs) p38 alpha and Erk2 with ATP-competitive inhibitors differentially, and in some cases divergently, modulates the abilities of these kinases to interact with upstream activators and deactivating phosphatases. Conformation-selective ligands are also able to modulate Erk2's ability to allosterically activate the MAPK phosphatase DUSP6, highlighting how ATP-competitive ligands can control noncatalytic kinase functions. Overall, these studies underscore the relationship between the ATP-binding and regulatory sites of MAPKs and provide insight into how ATP-competitive ligands can be designed to confer graded control over protein kinase function.
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