8s6i

Crystal structure of the human CDKL2 kinase domain with Compound 9

spinqualitylabelsall models 8s6i, resolution 1.72Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8s6i is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.72Å Ligands: A1H5G, CL, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CDKL2_HUMAN Publication Abstract from PubMed Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved cocrystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial-mesenchymal transition. Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2.,Bashore FM, Min SM, Chen X, Howell S, Rinderle CH, Morel G, Silvaroli JA, Wells CI, Bunnell BA, Drewry DH, Pabla NS, Ultanir SK, Bullock AN, Axtman AD ACS Med Chem Lett. 2024 Jul 3;15(8):1325-1333. doi: , 10.1021/acsmedchemlett.4c00219. eCollection 2024 Aug 8. PMID:39140040 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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