6GZD
Crystal structure of Human CSNK1A1 with A86
Summary for 6GZD
| Entry DOI | 10.2210/pdb6gzd/pdb |
| Descriptor | Casein kinase I isoform alpha, DIMETHYL SULFOXIDE, TRIETHYLENE GLYCOL, ... (8 entities in total) |
| Functional Keywords | ckia, casein kinase, kinase inhibitor, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 45224.63 |
| Authors | Ben-Neriah, Y.,Venkatachalam, A.,Minzel, W.,Fink, A.,Snir-Alkalay, I.,Vacca, J. (deposition date: 2018-07-03, release date: 2018-08-29, Last modification date: 2024-01-17) |
| Primary citation | Minzel, W.,Venkatachalam, A.,Fink, A.,Hung, E.,Brachya, G.,Burstain, I.,Shaham, M.,Rivlin, A.,Omer, I.,Zinger, A.,Elias, S.,Winter, E.,Erdman, P.E.,Sullivan, R.W.,Fung, L.,Mercurio, F.,Li, D.,Vacca, J.,Kaushansky, N.,Shlush, L.,Oren, M.,Levine, R.,Pikarsky, E.,Snir-Alkalay, I.,Ben-Neriah, Y. Small Molecules Co-targeting CKI alpha and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell, 175:171-185.e25, 2018 Cited by PubMed Abstract: CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2;Flt3 AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia. PubMed: 30146162DOI: 10.1016/j.cell.2018.07.045 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.28 Å) |
Structure validation
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