3LQ5

Structure of CDK9/CyclinT in complex with S-CR8

Summary for 3LQ5

• Entry DOI: 10.2210/pdb3lq5/pdb
• Related: 3BLH 3BLQ 3BLR
• Descriptor: Cell division protein kinase 9, Cyclin-T1, (2S)-2-({9-(1-methylethyl)-6-[(4-pyridin-2-ylbenzyl)amino]-9H-purin-2-yl}amino)butan-1-ol, ... (4 entities in total)
• Functional Keywords: transcriptional cdk-cyclin complex, phosphorylated, atp-binding, kinase, nucleotide-binding, nucleus, phosphoprotein, serine/threonine-protein kinase, transcription regulation, transferase, cell cycle, cell division, host-virus interaction, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P50750 O60563
• Total number of polymer chains: 2
• Total formula weight: 68605.04

Authors

Hole, A.J.,Endicott, J.A.,Baumli, S. (deposition date: 2010-02-08, release date: 2011-01-19, Last modification date: 2024-11-06)

Primary citation

Bettayeb, K.,Baunbak, D.,Delehouze, C.,Loaec, N.,Hole, A.J.,Baumli, S.,Endicott, J.A.,Douc-Rasy, S.,Benard, J.,Oumata, N.,Galons, H.,Meijer, L.
CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells
Genes Cancer, 1:369-380, 2010

PubMed Abstract: Neuroblastoma (NB), the most frequent extracranial solid tumor of children accounting for nearly 15% of all childhood cancer mortality, displays overexpression of antiapoptotic Bcl-2 and Mcl-1 in aggressive forms of the disease. The clinical phase 2 drug roscovitine (CYC202, seliciclib), a relatively selective inhibitor of cyclin-dependent kinases (CDKs), and CR8, a recently developed and more potent analog, induce concentration-dependent apoptotic cell death of NB cells (average IC(50) values: 24.2 µM and 0.4 µM for roscovitine and CR8, respectively). Both roscovitine and CR8 trigger rapid down-regulation of the short-lived survival factor Mcl-1 in the 9 investigated human NB cell lines. This effect was further analyzed in the human SH-SY5Y NB cell line. Down-regulation of Mcl-1 appears to depend on inhibition of CDKs rather than on interaction of roscovitine and CR8 with their secondary targets. CR8 is an adenosine triphosphate-competitive inhibitor of CDK9, and the structure of a CDK9/cyclin T/CR8 complex is described. Mcl-1 down-regulation occurs both at the mRNA and protein levels. This effect can be accounted for by a reduction in Mcl-1 protein synthesis, under stable Mcl-1 degradation conditions. Mcl-1 down-regulation is accompanied by a transient increase in free Noxa, a proapoptotic factor. Mcl-1 down-regulation occurs independently of the presence or up-regulation of p53 and of the MYCN status. Taken together, these results suggest that the clinical drug roscovitine and its novel analog CR8 induce apoptotic tumor cell death by down-regulating Mcl-1, a key survival factor expressed in all NB cell lines. CDK inhibition may thus constitute a new approach to treat refractory high-risk NB.

PubMed: 21779453
DOI: 10.1177/1947601910369817

Experimental method

X-RAY DIFFRACTION (3 Å)