7ZKX
SRPK2 IN COMPLEX WITH INHIBITOR
Summary for 7ZKX
| Entry DOI | 10.2210/pdb7zkx/pdb |
| Related | 7ZKS |
| Descriptor | SRSF protein kinase 2, N-[3-[[[2-(6-chloranyl-5-fluoranyl-1H-benzimidazol-2-yl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]-N-methyl-methanesulfonamide, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | serine/threonine-protein kinase, srpk2, nuclear protein, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 71518.03 |
| Authors | Graedler, U. (deposition date: 2022-04-13, release date: 2023-02-22, Last modification date: 2024-02-07) |
| Primary citation | Schroder, M.,Leiendecker, M.,Gradler, U.,Braun, J.,Blum, A.,Wanior, M.,Berger, B.T.,Kramer, A.,Muller, S.,Esdar, C.,Knapp, S.,Heinrich, T. MSC-1186, a Highly Selective Pan-SRPK Inhibitor Based on an Exceptionally Decorated Benzimidazole-Pyrimidine Core. J.Med.Chem., 66:837-854, 2023 Cited by PubMed Abstract: The highly conserved catalytic sites in protein kinases make it difficult to identify ATP competitive inhibitors with kinome-wide selectivity. Serendipitously, during a dedicated fragment campaign for the focal adhesion kinase (FAK), a scaffold that had lost its initial FAK affinity showed remarkable potency and selectivity for serine-arginine-protein kinases 1-3 (SRPK1-3). Non-conserved interactions with the uniquely structured hinge region of the SRPK family were the key drivers of the exclusive selectivity of the discovered fragment hit. Structure-guided medicinal chemistry efforts led to the SRPK inhibitor , which fulfills all hallmarks of a reversible chemical probe, including nanomolar cellular potency and excellent kinome-wide selectivity. The combination of with CDC2-like kinase (CLK) inhibitors showed additive attenuation of SR-protein phosphorylation compared to the single agents. and negative control () are chemical probes available via the Structural Genomics Consortium chemical probe program (https://www.sgc-ffm.uni-frankfurt.de/). PubMed: 36516476DOI: 10.1021/acs.jmedchem.2c01705 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.06 Å) |
Structure validation
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