3ddq
From Proteopedia
| Line 20: | Line 20: | ||
==About this Structure== | ==About this Structure== | ||
| - | 3DDQ is a | + | 3DDQ is a 4 chains structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3DDQ OCA]. |
==Reference== | ==Reference== | ||
| - | + | <ref group="xtra">PMID:18574471</ref><references group="xtra"/> | |
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
[[Category: Cyclin-dependent kinase]] | [[Category: Cyclin-dependent kinase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| - | [[Category: Protein complex]] | ||
[[Category: Echalier, A.]] | [[Category: Echalier, A.]] | ||
[[Category: Endicott, J A.]] | [[Category: Endicott, J A.]] | ||
| Line 47: | Line 46: | ||
[[Category: Transferase/cell cycle complex]] | [[Category: Transferase/cell cycle complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Feb 17 11:45:18 2009'' |
Revision as of 09:45, 17 February 2009
Structure of phosphorylated Thr160 CDK2/cyclin A in complex with the inhibitor roscovitine
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 Structure
3DDQ is a 4 chains structure of sequences from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Bettayeb K, Oumata N, Echalier A, Ferandin Y, Endicott JA, Galons H, Meijer L. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene. 2008 Oct 2;27(44):5797-807. Epub 2008 Jun 23. PMID:18574471 doi:10.1038/onc.2008.191
Page seeded by OCA on Tue Feb 17 11:45:18 2009
Categories: Bos taurus | Cyclin-dependent kinase | Homo sapiens | Echalier, A. | Endicott, J A. | Atp-binding | Cell cycle | Cell division | Cyclin | Cytoplasm | Kinase | Mitosis | Nucleotide-binding | Nucleus | Phosphoprotein | Phosphorylation | Polymorphism | Ser/thr protein kinase | Serine/threonine-protein kinase | Transferase | Transferase/cell cycle complex
