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. Epub 2014 May 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology*
  • Cinnamates / chemistry
  • Cinnamates / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / chemistry*
  • Protein Kinase C / metabolism*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Structure, Tertiary / drug effects
  • Structure-Activity Relationship


  • Biphenyl Compounds
  • Cinnamates
  • PS315
  • Protein Kinase Inhibitors
  • PKC-3 protein
  • Protein Kinase C

Associated data

  • PDB/4CT1
  • PDB/4CT2