Allosteric Regulation of Protein Kinase PKCζ by the N-Terminal C1 Domain and Small Compounds to the PIF-Pocket

• Published in: Chemistry & biology Vol. 18; no. 11; pp. 1463 - 1473
• Main Authors: Lopez-Garcia, Laura A., Schulze, Jörg O., Fröhner, Wolfgang, Zhang, Hua, Süß, Evelyn, Weber, Nadja, Navratil, Jeanette, Amon, Sabine, Hindie, Valerie, Zeuzem, Stefan, Jørgensen, Thomas J.D., Alzari, Pedro M., Neimanis, Sonja, Engel, Matthias, Biondi, Ricardo M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 23.11.2011; Elsevier
• Subjects: Allosteric Regulation; Allosteric Regulation - drug effects; Binding Sites; Biocatalysis; Biochemistry, Molecular Biology; Bioinformatics; Biological Physics; Cell Line, Tumor; Cellular Biology; Chemical Sciences; Computer Science; Cristallography; Humans; Life Sciences; NF-kappa B; NF-kappa B - metabolism; Physics; Protein Kinase C; Protein Kinase C - chemistry; Protein Kinase C - metabolism; Protein Structure, Tertiary; Signal Transduction; Small Molecule Libraries; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structural Biology
• ISSN: 1074-5521; 1879-1301
• DOI: 10.1016/j.chembiol.2011.08.010

Protein kinases are key mediators of cellular signaling, and therefore, their activities are tightly controlled. AGC kinases are regulated by phosphorylation and by N- and C-terminal regions. Here, we studied the molecular mechanism of inhibition of atypical PKCζ and found that the inhibition by the N-terminal region cannot be explained by a simple pseudosubstrate inhibitory mechanism. Notably, we found that the C1 domain allosterically inhibits PKCζ activity and verified an allosteric communication between the PIF-pocket of atypical PKCs and the binding site of the C1 domain. Finally, we developed low-molecular-weight compounds that bind to the PIF-pocket and allosterically inhibit PKCζ activity. This work establishes a central role for the PIF-pocket on the regulation of PKCζ and allows us to envisage development of drugs targeting the PIF-pocket that can either activate or inhibit AGC kinases. ► C1 domain allosterically inhibits the activity of the catalytic domain of PKCζ ► There is an allosteric communication between C1 domain and the PIF-pocket ► Small compounds that bind to the PIF-pocket allosterically inhibit PKCζ activity ► The PIF-pocket is a pharmacological target for activators and inhibitors of AGC kinases