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7n7m

From Proteopedia

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Current revision

Crystal Structure of PI5P4KIIAlpha complex with BI-2536

Structural highlights

7n7m 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 2.6Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PI42A_HUMAN Precursor B-cell acute lymphoblastic leukemia.

Function

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.^[1]

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^[2]

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

References

↑ Wilcox A, Hinchliffe KA. Regulation of extranuclear PtdIns5P production by phosphatidylinositol phosphate 4-kinase 2alpha. FEBS Lett. 2008 Apr 16;582(9):1391-4. doi: 10.1016/j.febslet.2008.03.022. Epub, 2008 Mar 24. PMID:18364242 doi:http://dx.doi.org/10.1016/j.febslet.2008.03.022
↑ Chen S, Chandra Tjin C, Gao X, Xue Y, Jiao H, Zhang R, Wu M, He Z, Ellman J, Ha Y. Pharmacological inhibition of PI5P4Kalpha/beta disrupts cell energy metabolism and selectively kills p53-null tumor cells. Proc Natl Acad Sci U S A. 2021 May 25;118(21). pii: 2002486118. doi:, 10.1073/pnas.2002486118. PMID:34001596 doi:http://dx.doi.org/10.1073/pnas.2002486118

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7n7m"

Categories: Homo sapiens | Large Structures | Chen S | Ha Y

@@ Line 3: / Line 3: @@
 <StructureSection load='7n7m' size='340' side='right'caption='[[7n7m]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7n7m]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N7M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N7M FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7n7m]] 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=7N7M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N7M FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R78:4-{[(7R)-8-CYCLOPENTYL-7-ETHYL-5-METHYL-6-OXO-5,6,7,8-TETRAHYDROPTERIDIN-2-YL]AMINO}-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>R78</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.6&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIP4K2A, PI5P4KA, PIP5K2, PIP5K2A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R78:4-{[(7R)-8-CYCLOPENTYL-7-ETHYL-5-METHYL-6-OXO-5,6,7,8-TETRAHYDROPTERIDIN-2-YL]AMINO}-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>R78</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/1-phosphatidylinositol-5-phosphate_4-kinase 1-phosphatidylinositol-5-phosphate 4-kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.149 2.7.1.149] </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=7n7m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n7m OCA], [https://pdbe.org/7n7m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n7m RCSB], [https://www.ebi.ac.uk/pdbsum/7n7m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n7m ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/PI42A_HUMAN PI42A_HUMAN]] Precursor B-cell acute lymphoblastic leukemia.
+[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>
+[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 ==
@@ Line 26: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: 1-phosphatidylinositol-5-phosphate 4-kinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Chen, S]]
+[[Category: Chen S]]
-[[Category: Ha, Y]]
+[[Category: Ha Y]]
-[[Category: Kinase]]
-[[Category: Transferase-transferase inhibitor complex]]

7n7m

From Proteopedia

Current revision

Crystal Structure of PI5P4KIIAlpha complex with BI-2536

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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