4YLJ
Crystal structure of DYRK1A in complex with 10-Iodo-substituted 11H-indolo[3,2-c]quinoline-6-carboxylic acid inhibitor 5j
Summary for 4YLJ
| Entry DOI | 10.2210/pdb4ylj/pdb |
| Related | 4YLK 4YLL |
| Descriptor | Dual specificity tyrosine-phosphorylation-regulated kinase 1A, TETRAETHYLENE GLYCOL, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | halogen, inhibitor, structural genomics, structural genomics consortium, sgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Nucleus : Q13627 |
| Total number of polymer chains | 4 |
| Total formula weight | 172198.99 |
| Authors | Chaikuad, A.,Falke, H.,Nowak, R.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Kunick, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2015-03-05, release date: 2015-03-25, Last modification date: 2023-11-15) |
| Primary citation | Falke, H.,Chaikuad, A.,Becker, A.,Loaec, N.,Lozach, O.,Abu Jhaisha, S.,Becker, W.,Jones, P.G.,Preu, L.,Baumann, K.,Knapp, S.,Meijer, L.,Kunick, C. 10-Iodo-11H-indolo[3,2-c]quinoline-6-carboxylic Acids Are Selective Inhibitors of DYRK1A. J.Med.Chem., 58:3131-3143, 2015 Cited by PubMed Abstract: The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site. PubMed: 25730262DOI: 10.1021/jm501994d PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.58 Å) |
Structure validation
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