2io6: Difference between revisions

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New page: left|200px<br /> <applet load="2io6" size="450" color="white" frame="true" align="right" spinBox="true" caption="2io6, resolution 2.20Å" /> '''Wee1 kinase complex...
 
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[[Image:2io6.gif|left|200px]]<br />
<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==
==Wee1 kinase complexed with inhibitor PD330961==
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.
<StructureSection load='2io6' size='340' side='right'caption='[[2io6]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2io6]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2IO6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IO6 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=330:9-HYDROXY-6-(3-HYDROXYPROPYL)-4-(2-METHOXYPHENYL)PYRROLO[3,4-C]CARBAZOLE-1,3(2H,6H)-DIONE'>330</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2io6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2io6 OCA], [https://pdbe.org/2io6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2io6 RCSB], [https://www.ebi.ac.uk/pdbsum/2io6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2io6 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/WEE1_HUMAN 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 ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/io/2io6_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2io6 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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) 0.057 microM) 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==
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. 2008 Jun;43(6):1276-96. Epub 2007 Aug 6. PMID:17869387<ref>PMID:17869387</ref>
2IO6 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].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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]
</div>
<div class="pdbe-citations 2io6" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Baker EN]]
[[Category: Baker, E.N.]]
[[Category: Dickson JM]]
[[Category: Dickson, J.M.]]
[[Category: Ivanovic I]]
[[Category: Ivanovic, I.]]
[[Category: Squire CJ]]
[[Category: Squire, C.J.]]
[[Category: 330]]
[[Category: protein-inhibitor complex]]
[[Category: transferase]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:46:31 2007''

Latest revision as of 13:14, 30 August 2023

Wee1 kinase complexed with inhibitor PD330961Wee1 kinase complexed with inhibitor PD330961

Structural highlights

2io6 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:
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

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) 0.057 microM) 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.

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. 2008 Jun;43(6):1276-96. Epub 2007 Aug 6. PMID:17869387[1]

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

References

  1. ↑ 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. 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. Eur J Med Chem. 2008 Jun;43(6):1276-96. Epub 2007 Aug 6. PMID:17869387 doi:10.1016/j.ejmech.2007.07.016

2io6, resolution 2.20Å

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