7n7o | pdb_00007n7o

Crystal Structure of PI5P4KIIAlpha complex with Palbociclib

spinqualitylabelsall models 7n7o, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7n7o 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 2.7Å Ligands: LQQ, SO4 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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