Sandbox Reserved 568

This Sandbox is Reserved from 05/22/2012, through 07/22/2012 for use in the course "BIOL 414" taught by Greg Buhrman at the North Carolina State University, Raleigh, NC USA. This reservation includes Sandbox Reserved 551 through Sandbox Reserved 590.

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Hi Priscilla, Here is your very own Proteopedia Page for pdb code: 3DDQ. Your presentation is scheduled for: June 18.

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Greg Buhrman

spinqualitylabelsall models PDB ID 3ddq Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
3ddq, resolution 1.80Å ()
Ligands:	,
Non-Standard Residues:
Gene:	CDK2 (Homo sapiens), CCNA2, CCNA (Bos taurus)
Activity:	Cyclin-dependent kinase, with EC number 2.7.11.22
Related:	3ddp
Structural annotation: Resources: InterPro : Ipr000719, Ipr002290, Ipr008271, Ipr011009, Ipr017441, Ipr017442, Ipr004367, Ipr006670, Ipr006671, Ipr011028, Ipr013763, Ipr014400, Ipr015453 Pfam : PF00069, PF00134, PF02984
Functional annotation: Cellular component: cyclin-dependent protein kinase holoenzyme complex cytosol cytoplasm nucleoplasm nucleus female pronucleus male pronucleus Biological process: G2/M transition of mitotic cell cycle traversing start control point of mitotic cell cycle positive regulation of cell proliferation mitosis regulation of DNA replication cell cycle protein amino acid phosphorylation DNA replication cell division positive regulation of transcription Molecular function: kinase activity histone kinase activity protein binding protein kinase activity identical protein binding ATP binding transferase activity nucleotide binding protein serine/threonine kinase activity cyclin-dependent protein kinase activity
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, PDBsum, RCSB
Coordinates:	save as pdb, mmCIF, xml

Structure of phosphorylated Thr160 CDK2/cyclin A in complex with the inhibitor roscovitineStructure of phosphorylated Thr160 CDK2/cyclin A in complex with the inhibitor roscovitine

Publication Abstract from PubMed

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Among the ten pharmacological inhibitors of cyclin-dependent kinases (CDKs) currently in clinical trials, the purine roscovitine (CYC202, Seliciclib) is undergoing phase 2 trials against non-small-cell lung and nasopharyngeal cancers. An extensive medicinal chemistry study, designed to generate more potent analogues of roscovitine, led to the identification of an optimal substitution at the N6 position (compound CR8). An extensive selectivity study (108 kinases) highlights the exquisite selectivity of CR8 for CDK1/2/3/5/7/9. CR8 was 2- to 4-fold more potent than (R)-roscovitine at inhibiting these kinases. Cocrystal structures of (R)-CR8 and (R)-roscovitine with pCDK2/cyclin A showed that both inhibitors adopt essentially identical positions. The cellular effects of CR8 and (R)-roscovitine were investigated in human neuroblastoma SH-SY5Y cells. CR8 inhibited the phosphorylation of CDK1 and 9 substrates, with a 25-50 times higher potency compared to (R)-roscovitine. CR8 was consistently more potent than (R)-roscovitine at inducing apoptotic cell death parameters: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium reduction (40-fold), lactate dehydrogenase release (35-fold), caspases activation (68-fold) and poly-(ADP-ribose)polymerase cleavage (50-fold). This improved cell death-inducing activity of CR8 over (R)-roscovitine was observed in 25 different cell lines. Altogether these results show that second-generation analogues of (R)-roscovitine can be designed with improved antitumor potential.

CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases., Bettayeb K, Oumata N, Echalier A, Ferandin Y, Endicott JA, Galons H, Meijer L, Oncogene. 2008 Oct 2;27(44):5797-807. Epub 2008 Jun 23. PMID:18574471

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

About this StructureAbout this Structure

3DDQ is a 4 chains structure of sequences from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

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