9PC1

Co-crystal structure of the cAMP-dependent protein kinase catalytic subunit alpha with the inhibitor BLU0588

This is a non-PDB format compatible entry.

Summary for 9PC1

• Entry DOI: 10.2210/pdb9pc1/pdb
• Descriptor: cAMP-dependent protein kinase catalytic subunit alpha, cAMP-dependent protein kinase inhibitor alpha, (4S)-2-METHYL-2,4-PENTANEDIOL, ... (5 entities in total)
• Functional Keywords: phosphotransferase, transferase
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 2
• Total formula weight: 43310.32

Authors

Bruystens, J.G.H.,Taylor, S.S.,Wu, J. (deposition date: 2025-06-26, release date: 2026-05-13, Last modification date: 2026-05-20)

Primary citation

Bruystens, J.G.H.,Wu, J.,Tan, G.,Bertinetti, D.,Zenn, H.M.,Zimmermann, B.,Chen, L.,Kockenberger, J.,Massaro, F.,Sankaran, B.,Walters, M.S.,Veglia, G.,Ferguson, F.M.,Herberg, F.W.,Taylor, S.S.
A PKA-selective inhibitor captures an open but more ordered conformation of the PKA catalytic subunit.
Proc.Natl.Acad.Sci.USA, 123:e2536312123-e2536312123, 2026

PubMed Abstract: The structure of the catalytic subunit of cAMP-dependent protein kinase (PKA-C), a prototype for the protein kinase superfamily, laid the foundation for the development of targeted kinase inhibitors. Here we describe the structure and biophysical characterization of a PKA-C complex with BLU0588, a small PKA-selective inhibitor. The high-resolution crystal structure not only captures the inhibitor's unusual T-shaped geometry, but also shows how the four rings of BLU0588 serve as surrogates for ATP's adenosine and phosphate-organizing sites. Each site contains two subsites. BLU0588's planar azaindole and pyridine rings, which are buried beneath the glycine-rich loop in a hydrophobic shell at the base of the active site cleft, fill the adenine and ribose subsites. In contrast, BLU0588's indane and pyrrolidine rings fill the phosphate-organizing site. The indane ring occupies the α/β-phosphate organizing site while the pyrrolidine ring fills the Mg/γ-phosphate organizing site. The structure also shows how BLU0588 nucleates an open but stable conformation of the entire hydrophobic architecture of the N- and C-lobes. In addition to potently blocking phosphoryl transfer activity, BLU0588 also abolishes the synergistic high-affinity binding of the physiological pseudosubstrate inhibitor, protein kinase inhibitor. The residence time of BLU0588, measured by surface plasmon residence, contributes to its picomolar affinity and is distinct from H89, a commonly used but more promiscuous PKA inhibitor. These molecular insights provide a valuable framework for dissecting the organization of the active site cleft as well as different strategies for the rational design of more potent and selective kinase inhibitors in general.

PubMed: 42096309
DOI: 10.1073/pnas.2536312123

Experimental method

X-RAY DIFFRACTION (1.552 Å)