2io6
From Proteopedia
Line 1: | Line 1: | ||
[[Image:2io6.jpg|left|200px]] | [[Image:2io6.jpg|left|200px]] | ||
- | + | <!-- | |
- | + | The line below this paragraph, containing "STRUCTURE_2io6", creates the "Structure Box" on the page. | |
- | + | You may change the PDB parameter (which sets the PDB file loaded into the applet) | |
- | + | or the SCENE parameter (which sets the initial scene displayed when the page is loaded), | |
- | + | or leave the SCENE parameter empty for the default display. | |
- | | | + | --> |
- | | | + | {{STRUCTURE_2io6| PDB=2io6 | SCENE= }} |
- | + | ||
- | + | ||
- | }} | + | |
'''Wee1 kinase complexed with inhibitor PD330961''' | '''Wee1 kinase complexed with inhibitor PD330961''' | ||
Line 30: | Line 27: | ||
[[Category: Ivanovic, I.]] | [[Category: Ivanovic, I.]] | ||
[[Category: Squire, C J.]] | [[Category: Squire, C J.]] | ||
- | [[Category: | + | [[Category: Protein-inhibitor complex]] |
- | [[Category: | + | [[Category: Transferase]] |
- | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:42:42 2008'' | |
- | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + |
Revision as of 04:42, 4 May 2008
Wee1 kinase complexed with inhibitor PD330961
Overview
A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057muM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.
About this Structure
2IO6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases., Smaill JB, Baker EN, Booth RJ, Bridges AJ, Dickson JM, Dobrusin EM, Ivanovic I, Kraker AJ, Lee HH, Lunney EA, Ortwine DF, Palmer BD, Quin J 3rd, Squire CJ, Thompson AM, Denny WA, Eur J Med Chem. 2007 Aug 6;. PMID:17869387 Page seeded by OCA on Sun May 4 07:42:42 2008