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Chem Biol. 2014 May 22;21(5):628-35. doi: 10.1016/j.chembiol.2014.02.016. Epub 2014 Apr 3.

Conformation-selective ATP-competitive inhibitors control regulatory interactions and noncatalytic functions of mitogen-activated protein kinases.

Author information

1
Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
2
Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
3
Department of Chemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: maly@chem.washington.edu.

Abstract

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) p38α 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.

PMID:
24704509
PMCID:
PMC4123212
DOI:
10.1016/j.chembiol.2014.02.016
[Indexed for MEDLINE]
Free PMC Article

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