Abstract
Protein kinase C (PKC) isozymes play a critical role in many signal transduction pathways and are also main targets of tumor-promoting phorbol esters. Conventional and novel PKC isozymes contain two cysteine-rich C 1 domains (C 1 A and C 1 B), both of which are candidates for phorbol ester binding sites. These C 1 domains of about 50-70 amino acids were synthesized by an Fmocsolid phase strategy, and were successfully folded by zinc treatment. We measured the dissociation constants (Kd's) of [3H] phorbol-12, 13-dibutyrate for all PKC C 1 peptides. Most of the C 1 peptides showed strong PDBu binding affinities with Kd's in the nanomolar range (0.45-7.4 nM) comparable to the respective whole PKC isozymes. The resultant C 1 peptide library can be used to screen for new ligands with PKC isozyme and importantly C 1 domain selectivity. We have recently developed a new lactone analogue of benzolactams (6) which shows significant selectivity in the PKCη-C 1 B binding on the basis of the structure-activity relationship of teleocidin-type tumor promoters.
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