6b3e

Crystal structure of human CDK12/CyclinK in complex with an inhibitorCrystal structure of human CDK12/CyclinK in complex with an inhibitor

Structural highlights 6b3e is a 4 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 3.06Å Ligands: , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CDK12_HUMAN Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2. Function CDK12_HUMAN Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogn inhibitors. Publication Abstract from PubMed CDK12 knockdown via siRNA reduces transcription of DNA damage response genes and sensitizes BRCA wild type cells to PARP inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5. Further structure guided optimization delivered a series of selective CDK12 inhibitors, including compound 7. Profiling of this compound across CDK9, 7, 2 and 1 at high ATP concentration, single point kinase panel screening against 352 targets at 0.1 microM, and proteomics via kinase affinity matrix technology demonstrated selectivity. This series of compounds inhibit phosphorylation of Ser2 on the C-terminal repeat domain of RNA pol II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells. Structure Based Design of Selective Non-covalent CDK12 Inhibitors.,Johannes J, Denz CR, Su N, Wu A, Impastato AC, Mlynarski S, Varnes JG, Prince DB, Cidado J, Gao N, Haddrick M, Jones NH, Li S, Li X, Liu Y, Nguyen TB, O'Connell N, Rivers E, Robbins DW, Tomlinson R, Yao T, Ferguson AD, Lamb ML, Manchester JI, Guichard S ChemMedChem. 2017 Dec 20. doi: 10.1002/cmdc.201700695. PMID:29266803 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cyclin 3D structures Cyclin-dependent kinase 3D structures

spinqualitylabelsall models 6b3e, resolution 3.06Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image