Figure 1.

Design of a stapled pseudosubstrate inhibitor for the catalytic subunit of Protein Kinase A (PKA-C): (a) Crystal structure of PKA-C (gray, PDB ID: 1ATP) bound to a Protein Kinase Inhibitor (PKI^5–24 ) (IP20, red). The side chains of Arg 18 and 19 are shown and are critical for pseudosubstrate inhibition; (b) Peptide stapling was performed on-resin with ring-closing metathesis chemistry using the 1st Generation Grubbs catalyst to introduce a staple in the N-terminal alpha-helix; and (c) An analog of IP20 is designed by incorporating a hydrocarbon staple into the N-terminus of the PKI-derived peptide to serve as a non-catalytic, allosteric inhibitor for PKA-C. Structures were rendered using PyMol.