2io6: Difference between revisions

Revision as of 12:12, 23 January 2008

Wee1 kinase complexed with inhibitor PD330961

OverviewOverview

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 StructureAbout this Structure

2IO6 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Transferase, with EC number 2.7.10.2 Full crystallographic information is available from OCA.

ReferenceReference

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 Wed Jan 23 11:12:48 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:2io6.gif|left|200px]]<br />
+[[Image:2io6.jpg|left|200px]]<br /><applet load="2io6" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2io6" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2io6, resolution 2.20&Aring;" />
 '''Wee1 kinase complexed with inhibitor PD330961'''<br />
 ==Overview==
-Phosphorylation is critical to regulation of the eukaryotic cell cycle., Entry to mitosis is triggered by the cyclin-dependent kinase CDK1 (Cdc2), which is inactivated during the preceding S and G2 phases by, phosphorylation of T14 and Y15. Two homologous kinases, Wee1, which, phosphorylates Y15, and Myt1, which phosphorylates both T14 and Y15, mediate this inactivation. We have determined the crystal structure of the, catalytic domain of human somatic Wee1 (Wee1A) complexed with an, active-site inhibitor at 1.8 A resolution. Although Wee1A is functionally, a tyrosine kinase, in sequence and structure it most closely resembles, serine/threonine kinases such as Chk1 and cAMP kinases. The crystal, structure shows that although the catalytic site closely resembles that of, other protein kinases, the activation segment contains Wee1-specific, features that maintain it in an active conformation and, together with a, key substitution in its glycine-rich loop, help determine its substrate, specificity.
+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==
-IO6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 330 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2IO6 OCA].
+IO6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=330:'>330</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IO6 OCA].
 ==Reference==
-Structure and inhibition of the human cell cycle checkpoint kinase, Wee1A kinase: an atypical tyrosine kinase with a key role in CDK1 regulation., Squire CJ, Dickson JM, Ivanovic I, Baker EN, Structure. 2005 Apr;13(4):541-50. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15837193 15837193]
+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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17869387 17869387]
 [[Category: Homo sapiens]]
-[[Category: Non-specific protein-tyrosine kinase]]
 [[Category: Single protein]]
+[[Category: Transferase]]
 [[Category: Baker, E.N.]]
 [[Category: Dickson, J.M.]]
@@ Line 23: / Line 22: @@
 [[Category: transferase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:46:31 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:12:48 2008''