ATP competitive protein kinase C inhibitors demonstrate distinct state-dependent inhibition

• Published in: PloS one Vol. 6; no. 10; p. e26338
• Main Authors: Smith, Ida M, Hoshi, Naoto
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.10.2011; Public Library of Science (PLoS)
• Subjects: Activation; Adenosine Triphosphate - metabolism; Animals; ATP; Binding, Competitive; Biology; Bisindolylmaleimide I; Competition; Deactivation; Enzymes; Humans; Indoles; Inhibitors; Kinases; Kinetics; Maleimides; Peptides; Phosphatase; Phosphorylation; Protein Conformation; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase Inhibitors - pharmacology; Protein kinases; Protein Stability; Proteins; Translocation; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0026338

We previously reported that some ATP competitive protein kinase C (PKC) inhibitors are either competitive or uncompetitive inhibitors with respect to substrate peptides. In this report, we demonstrate how the interactions between PKC and inhibitors change PKC activation kinetics. A substrate competitive inhibitor, bisindolylmaleimide I, targets activated PKC and stabilizes PKC in the activated conformation. This leads to transient activation and prolonged deactivation of PKC in the presence of bisindolylmaleimide I. In contrast, an uncompetitive substrate inhibitor, bisindolylmaleimide IV, targets quiescent PKC and stabilizes PKC in the quiescent conformation, which generates slower activation and suppressed translocation upon activation of PKC.