Rational design of a new C-myristylamido peptide exerting potent and selective PKC inhibitory activity.
A 3D model of the catalytic domain of PKC was built based on the X-ray structure of the homologous PKA enzyme. The two enzymes were found to have similar general architecture although differing for the number of negatively charged clusters and their location near the phosphorylation site. These differences were consistent with the charge requirements deduced from the consensus sequence of PKC and PKA substrates. A Myristyl Binding Site (MBS) was found in the PKC model between helix C and sheets 8 and 9. The identification of this MBS allowed the rationalization of the results obtained with N-myristoylated peptide inhibitors and, above all, the design of ITF1671 (H-RFARKGALRQKN-CONH-Myr), a new C-myristylamido peptide, which exerted one of the most potent inhibitory activity against PKC and PKM known to-date.
Zaliani
A
A
Italfarmaco Research Centre, Milan, Italy.
Gromo
G
G
Pinori
M
M
Mascagni
P
P
D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009227:Myristic Acids / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017433:Protein Structure, Secondary
C103386:ITF1671 protein, synthetic; D009227:Myristic Acids; D009842:Oligopeptides; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C