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==Crystal Structure of PI5P4KIIAlpha complex with Volasertib== | ==Crystal Structure of PI5P4KIIAlpha complex with Volasertib== | ||
<StructureSection load='7n7n' size='340' side='right'caption='[[7n7n]]' scene=''> | <StructureSection load='7n7n' size='340' side='right'caption='[[7n7n]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N7N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N7N FirstGlance]. <br> | <table><tr><td colspan='2'>[[7n7n]] 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=7N7N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N7N FirstGlance]. <br> | ||
</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=7n7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n7n OCA], [https://pdbe.org/7n7n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n7n RCSB], [https://www.ebi.ac.uk/pdbsum/7n7n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n7n ProSAT]</span></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]] 2.3Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IBI:N-{TRANS-4-[4-(CYCLOPROPYLMETHYL)PIPERAZIN-1-YL]CYCLOHEXYL}-4-{[(7R)-7-ETHYL-5-METHYL-8-(1-METHYLETHYL)-6-OXO-5,6,7,8-TETRAHYDROPTERIDIN-2-YL]AMINO}-3-METHOXYBENZAMIDE'>IBI</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7n7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n7n OCA], [https://pdbe.org/7n7n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n7n RCSB], [https://www.ebi.ac.uk/pdbsum/7n7n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n7n ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/PI42A_HUMAN PI42A_HUMAN] Precursor B-cell acute lymphoblastic leukemia. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PI42A_HUMAN PI42A_HUMAN] Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2. May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation. May negatively regulate insulin-stimulated glucose uptake by lowering the levels of PtdIns5P. May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size.<ref>PMID:18364242</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Most human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase alpha and beta (PI5P4Kalpha and PI5P4Kbeta) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4Kalpha/beta kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4Kalphabeta inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer drugs. | |||
Pharmacological inhibition of PI5P4Kalpha/beta disrupts cell energy metabolism and selectively kills p53-null tumor cells.,Chen S, Chandra Tjin C, Gao X, Xue Y, Jiao H, Zhang R, Wu M, He Z, Ellman J, Ha Y Proc Natl Acad Sci U S A. 2021 May 25;118(21). pii: 2002486118. doi:, 10.1073/pnas.2002486118. PMID:34001596<ref>PMID:34001596</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7n7n" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chen S]] | [[Category: Chen S]] | ||
[[Category: Ha Y]] | [[Category: Ha Y]] | ||
Latest revision as of 18:22, 4 October 2023
Crystal Structure of PI5P4KIIAlpha complex with VolasertibCrystal Structure of PI5P4KIIAlpha complex with Volasertib
Structural highlights
DiseasePI42A_HUMAN Precursor B-cell acute lymphoblastic leukemia. FunctionPI42A_HUMAN Catalyzes the phosphorylation of phosphatidylinositol 5-phosphate (PtdIns5P) on the fourth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). May exert its function by regulating the levels of PtdIns5P, which functions in the cytosol by increasing AKT activity and in the nucleus signals through ING2. May regulate the pool of cytosolic PtdIns5P in response to the activation of tyrosine phosphorylation. May negatively regulate insulin-stimulated glucose uptake by lowering the levels of PtdIns5P. May be involved in thrombopoiesis, and the terminal maturation of megakaryocytes and regulation of their size.[1] Publication Abstract from PubMedMost human cancer cells harbor loss-of-function mutations in the p53 tumor suppressor gene. Genetic experiments have shown that phosphatidylinositol 5-phosphate 4-kinase alpha and beta (PI5P4Kalpha and PI5P4Kbeta) are essential for the development of late-onset tumors in mice with germline p53 deletion, but the mechanism underlying this acquired dependence remains unclear. PI5P4K has been previously implicated in metabolic regulation. Here, we show that inhibition of PI5P4Kalpha/beta kinase activity by a potent and selective small-molecule probe disrupts cell energy homeostasis, causing AMPK activation and mTORC1 inhibition in a variety of cell types. Feedback through the S6K/insulin receptor substrate (IRS) loop contributes to insulin hypersensitivity and enhanced PI3K signaling in terminally differentiated myotubes. Most significantly, the energy stress induced by PI5P4Kalphabeta inhibition is selectively toxic toward p53-null tumor cells. The chemical probe, and the structural basis for its exquisite specificity, provide a promising platform for further development, which may lead to a novel class of diabetes and cancer drugs. Pharmacological inhibition of PI5P4Kalpha/beta disrupts cell energy metabolism and selectively kills p53-null tumor cells.,Chen S, Chandra Tjin C, Gao X, Xue Y, Jiao H, Zhang R, Wu M, He Z, Ellman J, Ha Y Proc Natl Acad Sci U S A. 2021 May 25;118(21). pii: 2002486118. doi:, 10.1073/pnas.2002486118. PMID:34001596[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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