2. Academic Validation
  3. Molecular mechanism of regulation of the atypical protein kinase C by N-terminal domains and an allosteric small compound

Molecular mechanism of regulation of the atypical protein kinase C by N-terminal domains and an allosteric small compound

  • Chem Biol. 2014 Jun 19;21(6):754-65. doi: 10.1016/j.chembiol.2014.04.007.
Hua Zhang 1,  Sonja Neimanis 1,  Laura A Lopez-Garcia 1,  José M Arencibia 1,  Sabine Amon 2,  Adriana Stroba 3,  Stefan Zeuzem 1,  Ewgen Proschak 4,  Holger Stark 5,  Angelika F Bauer 1,  Katrien Busschots 1,  Thomas J D Jørgensen 2,  Matthias Engel 3,  Jörg O Schulze 1,  Ricardo M Biondi 6
Affiliations

Affiliations

  • 1 Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
  • 2 Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
  • 3 Department of Pharmaceutical and Medicinal Chemistry, University of Saarland, 66041 Saarbrücken, Germany.
  • 4 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
  • 5 Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438 Frankfurt, Germany.
  • 6 Research Group PhosphoSites, Department of Internal Medicine I, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Electronic address: [email protected].
PMID: 24836908 DOI: 10.1016/j.chembiol.2014.04.007
Abstract

Protein kinases play important regulatory roles in cells and organisms. Therefore, they are subject to specific and tight mechanisms of regulation that ultimately converge on the catalytic domain and allow the kinases to be activated or inhibited only upon the appropriate stimuli. AGC protein kinases have a pocket in the catalytic domain, the PDK1-interacting fragment (PIF)-pocket, which is a key mediator of the activation. We show here that helix αC within the PIF-pocket of atypical protein kinase C (aPKC) is the target of the interaction with its inhibitory N-terminal domains. We also provide structural evidence that the small compound PS315 is an allosteric inhibitor that binds to the PIF-pocket of aPKC. PS315 exploits the physiological dynamics of helix αC for its binding and allosteric inhibition. The results will support research on allosteric mechanisms and selective drug development efforts against PKC isoforms.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124308
    PKC Inhibitor
    PKC