Targeted disruption of AKAP signaling complexes with constrained peptides. a) AKAP signaling complexes can scaffold a variety of different proteins in addition to PKA including adenylyl cyclases (ACs), phosphodiesterases (PDEs), substrates and protein phosphatases (PPases). The tetrameric holoenzyme complex interacts with an AKAP-derived helix through its regulatory domains. b) A hydrocarbon stapled peptide, STAD-2, was previously shown to selectively inhibit RII:AKAP complexes and was used as a template for library design. c) The constrained peptide is designed to inhibit the binding groove formed in the docking/dimerization (D/D) domain of the R-subunit of PKA (gray) that serves as a docking site for AKAPs (teal). In the STAD-2 sequence above, amino acids facing the D/D domain are depicted in red and solvent exposed amino acids are shown in teal.