8bju: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[8bju]] 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=8BJU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BJU FirstGlance]. <br>
<table><tr><td colspan='2'>[[8bju]] 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=8BJU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BJU FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QT9:2-(2-methoxyphenyl)-6-[[4-(4-methylpiperazin-1-yl)phenyl]amino]-1-[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]pyrazolo[3,4-d]pyrimidin-3-one'>QT9</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.53&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QT9:2-(2-methoxyphenyl)-6-[[4-(4-methylpiperazin-1-yl)phenyl]amino]-1-[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]pyrazolo[3,4-d]pyrimidin-3-one'>QT9</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=8bju FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bju OCA], [https://pdbe.org/8bju PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bju RCSB], [https://www.ebi.ac.uk/pdbsum/8bju PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bju ProSAT]</span></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=8bju FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bju OCA], [https://pdbe.org/8bju PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bju RCSB], [https://www.ebi.ac.uk/pdbsum/8bju PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bju ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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.
[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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Wee1 is a tyrosine kinase that is highly expressed in several cancer types. Wee1 inhibition can lead to suppression of tumor cell proliferation and sensitization of cells to the effects of DNA-damaging agents. AZD1775 is a nonselective Wee1 inhibitor for which myelosuppression has been observed as a dose-limiting toxicity. We have applied structure-based drug design (SBDD) to rapidly generate highly selective Wee1 inhibitors that demonstrate better selectivity than AZD1775 against PLK1, which is known to cause myelosuppression (including thrombocytopenia) when inhibited. While selective Wee1 inhibitors described herein still achieved in vitro antitumor efficacy, thrombocytopenia was still observed in vitro.
Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression.,Guler S, DiPoto MC, Crespo A, Caldwell R, Doerfel B, Grossmann N, Ho K, Huck B, Jones CC, Lan R, Musil D, Potnick J, Schilke H, Sherer B, Simon S, Sirrenberg C, Zhang Z, Liu-Bujalski L ACS Med Chem Lett. 2023 Apr 7;14(5):566-576. doi: 10.1021/acsmedchemlett.2c00481. , eCollection 2023 May 11. PMID:37197456<ref>PMID:37197456</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8bju" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>

Latest revision as of 11:18, 7 February 2024

HUMAN WEE1 KINASE IN COMPLEX WITH INHIBITOR 1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-2-yl]-2-(2-methoxy-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-oneHUMAN WEE1 KINASE IN COMPLEX WITH INHIBITOR 1-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-2-yl]-2-(2-methoxy-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-phenylamino]-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one

Structural highlights

8bju 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 1.53Å
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.

8bju, resolution 1.53Å

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