Development of novel C1 domain ligands of protein kinase C to clarify the precise structure and activation mechanism

Protein kinase C (PKC) is a family of enzymes which play important roles in intracellular signal transduction. We designed a series of novel PKC ligands having an isobenzofuranone (IB) template, based on the proposed interaction of DAG (1,2-diacyl-sn-glycerol) with PKC. Since interaction of the hydrophobic alkyl chain of the IB derivatives with lipid membrane is expected to be critical for the PKC activation, we were interested in the synthesis of the IB derivatives having the hydrophobic alkyl chain at various positions of the benzene ring. Effects of these synthetic ligands on the PKCa phosphorylation activity were examined. Surprisingly, 4-substitued derivative showed no activation of PKCα even at high concentration at which significant binding to PKCα was observed. These results suggest that position of the hydrophobic chain is critical for the PKC activation.