5IZJ

Complex of PKA with the bisubstrate protein kinase inhibitor ARC-1411

Summary for 5IZJ

• Entry DOI: 10.2210/pdb5izj/pdb
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, 47P-AZ1-DAR-DAR, 47P-AZ1-DAR-DAR-DAR, ... (6 entities in total)
• Functional Keywords: protein kinase, inhibitor, bisubstrate, oligoarginine, pka, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 85993.79

Authors

Pflug, A.,Enkvist, E.,Uri, A.,Engh, R.A. (deposition date: 2016-03-25, release date: 2016-07-20, Last modification date: 2025-04-09)

Primary citation

Ivan, T.,Enkvist, E.,Viira, B.,Manoharan, G.B.,Raidaru, G.,Pflug, A.,Alam, K.A.,Zaccolo, M.,Engh, R.A.,Uri, A.
Bifunctional Ligands for Inhibition of Tight-Binding Protein-Protein Interactions.
Bioconjug.Chem., 27:1900-1910, 2016

PubMed Abstract: The acknowledged potential of small-molecule therapeutics targeting disease-related protein-protein interactions (PPIs) has promoted active research in this field. The strategy of using small molecule inhibitors (SMIs) to fight strong (tight-binding) PPIs tends to fall short due to the flat and wide interfaces of PPIs. Here we propose a biligand approach for disruption of strong PPIs. The potential of this approach was realized for disruption of the tight-binding (KD = 100 pM) tetrameric holoenzyme of cAMP-dependent protein kinase (PKA). Supported by X-ray analysis of cocrystals, bifunctional inhibitors (ARC-inhibitors) were constructed that simultaneously associated with both the ATP-pocket and the PPI interface area of the catalytic subunit of PKA (PKAc). Bifunctional inhibitor ARC-1411, possessing a KD value of 3 pM toward PKAc, induced the dissociation of the PKA holoenzyme with a low-nanomolar IC50, whereas the ATP-competitive inhibitor H89 bound to the PKA holoenzyme without disruption of the protein tetramer.

PubMed: 27389935
DOI: 10.1021/acs.bioconjchem.6b00293

Experimental method

X-RAY DIFFRACTION (1.85 Å)