3bi6

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Wee1 kinase complex with inhibitor PD352396

Structural highlights

3bi6 is a 1 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 2.2Å
Ligands:396, CL
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

WEE1_HUMAN Acts as a negative regulator of entry into mitosis (G2 to M transition) by protecting the nucleus from cytoplasmically activated cyclin B1-complexed CDK1 before the onset of mitosis by mediating phosphorylation of CDK1 on 'Tyr-15'. Specifically phosphorylates and inactivates cyclin B1-complexed CDK1 reaching a maximum during G2 phase and a minimum as cells enter M phase. Phosphorylation of cyclin B1-CDK1 occurs exclusively on 'Tyr-15' and phosphorylation of monomeric CDK1 does not occur. Its activity increases during S and G2 phases and decreases at M phase when it is hyperphosphorylated. A correlated decrease in protein level occurs at M/G1 phase, probably due to its degradation.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Pyrrolo[3,4-c]carbazoles bearing solubilising basic side chains at the 8-position retain potent Wee1 and Chk1 inhibitory properties in isolated enzyme assays, and evidence of G2/M checkpoint abrogation in several cellular assays. Co-crystal structure studies confirm that the primary binding to the Wee1 enzyme is as described previously, with the C-8 side chains residing in an area of bulk tolerance.

Synthesis and structure-activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases.,Smaill JB, Lee HH, Palmer BD, Thompson AM, Squire CJ, Baker EN, Booth RJ, Kraker A, Hook K, Denny WA Bioorg Med Chem Lett. 2008 Feb 1;18(3):929-33. Epub 2008 Jan 11. PMID:18191399[1]

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

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Citations
3 reviews cite this structure
Improving gemcitabine-mediated radiosensitization using molecularly targeted therapy: a review.
Morgan et al. (2008)
2 more
5 other articles
No citations found

References

  1. ↑ Smaill JB, Lee HH, Palmer BD, Thompson AM, Squire CJ, Baker EN, Booth RJ, Kraker A, Hook K, Denny WA. Synthesis and structure-activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases. Bioorg Med Chem Lett. 2008 Feb 1;18(3):929-33. Epub 2008 Jan 11. PMID:18191399 doi:10.1016/j.bmcl.2007.12.046

Contents


PDB ID 3bi6

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OCA

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