Deciphering the Structural Basis of Eukaryotic Protein Kinase Regulation

摘要: Eukaryotic protein kinases (EPKs) regulate numerous signaling processes by phosphorylating targeted substrates through the highly conserved catalytic domain. Our previous computational studies proposed a model stating that properly assembled nonlinear motif termed Regulatory (R) spine is essential for activity of EPKs. Here we define required intramolecular interactions and biochemical properties R-spine newly identified "Shell" surrounds using site-directed mutagenesis various in vitro phosphoryl transfer assays cyclic AMP-dependent kinase as representative entire kinome. Analysis 172 available Apo EPK structures data bank (PDB) revealed four unique structural conformations correspond with inactivation Elucidating molecular entities activation EPKs identification these inactive opens new avenues design efficient therapeutic inhibitors.