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ATP Competitive Protein Kinase C Inhibitors Demonstrate Distinct State-Dependent Inhibition Ida M. Smith, Naoto Hoshi* Department of Pharmacology, University of California Irvine, Irvine, California, United States of America Abstract 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. Citation: Smith IM, Hoshi N (2011) ATP Competitive Protein Kinase C Inhibitors Demonstrate Distinct State-Dependent Inhibition. PLoS ONE 6(10): e26338. doi:10.1371/journal.pone.0026338 Editor: Adrian John Harwood, Cardiff University, United Kingdom Received April 28, 2011; Accepted September 25, 2011; Published October 17, 2011 Copyright: 2011 Smith, Hoshi. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (grant NS067288). The funders had no role in study design, data collec