Publication Abstract from PubMed
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) p38alpha 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.
Conformation-Selective ATP-Competitive Inhibitors Control Regulatory Interactions and Noncatalytic Functions of Mitogen-Activated Protein Kinases.,Hari SB, Merritt EA, Maly DJ Chem Biol. 2014 Apr 2. pii: S1074-5521(14)00075-1. doi:, 10.1016/j.chembiol.2014.02.016. PMID:24704509[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
