9RE2
Crystal Structure of the Protein-Kinase A catalytic subunit from Cricetulus griseus in complex with F058
This is a non-PDB format compatible entry.
Summary for 9RE2
| Entry DOI | 10.2210/pdb9re2/pdb |
| Descriptor | cAMP-dependent protein kinase catalytic subunit alpha, DIMETHYL SULFOXIDE, DI(HYDROXYETHYL)ETHER, ... (5 entities in total) |
| Functional Keywords | serine-threonine kinase, small molecules, ligand binding, fragment-based drug discovery, transferase |
| Biological source | Cricetulus griseus (Chinese hamster) |
| Total number of polymer chains | 1 |
| Total formula weight | 41606.41 |
| Authors | Ruf, M.,Mueller, J.M.,Wolter, M.,Glinca, S.,Klebe, G. (deposition date: 2025-06-03, release date: 2025-12-31, Last modification date: 2026-01-07) |
| Primary citation | Santura, A.,Muller, J.,Wolter, M.,Tutzschky, I.C.,Ruf, M.,Metz, A.,Sandner, A.,Merkl, S.,Klebe, G.,Glinca, S.,Czodrowski, P. Natural Product-like Fragments Unlock Novel Chemotypes for a Kinase Target─Exploring Options beyond the Flatland. J.Chem.Inf.Model., 2025 Cited by PubMed Abstract: In this study, we utilized a high-performance soaking system of protein kinase A (PKA) to perform a crystallographic screening of a natural product-like fragment library. We resolved 36 fragment-bound structures, corresponding to a hit rate of 41%. Nine fragments bound within the ATP site, nine peripherally, and 18 interacted with both the ATP and peripheral sites. One fragment binds to the same site as the approved allosteric kinase inhibitor asciminib, while another induces an unexpected conformational change. Systematic database mining revealed that both the fragments and their natural product parents have not been previously associated with PKA or kinase activity. A scaffold/chemotype analysis further underscored their novelty. Cheminformatics analyses confirmed that these fragments occupy a distinct chemical space, enriched in saturation, spatial complexity and molecular three-dimensional character compared to kinase binders from reference data sets. These properties have previously been linked to increased selectivity, reduced CYP450 inhibition, and higher overall clinical success rates. PubMed: 41430555DOI: 10.1021/acs.jcim.5c01952 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.68 Å) |
Structure validation
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