6osp

From Proteopedia

Crystal Structure Analysis of PIP4K2A

PDB ID 6osp

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Structural highlights

6osp is a 2 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 2.21Å
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

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kalpha/beta/gamma. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors.,Sivakumaren SC, Shim H, Zhang T, Ferguson FM, Lundquist MR, Browne CM, Seo HS, Paddock MN, Manz TD, Jiang B, Hao MF, Krishnan P, Wang DG, Yang TJ, Kwiatkowski NP, Ficarro SB, Cunningham JM, Marto JA, Dhe-Paganon S, Cantley LC, Gray NS Cell Chem Biol. 2020 Mar 3. pii: S2451-9456(20)30067-2. doi:, 10.1016/j.chembiol.2020.02.003. PMID:32130941^[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
↑ Sivakumaren SC, Shim H, Zhang T, Ferguson FM, Lundquist MR, Browne CM, Seo HS, Paddock MN, Manz TD, Jiang B, Hao MF, Krishnan P, Wang DG, Yang TJ, Kwiatkowski NP, Ficarro SB, Cunningham JM, Marto JA, Dhe-Paganon S, Cantley LC, Gray NS. Targeting the PI5P4K Lipid Kinase Family in Cancer Using Covalent Inhibitors. Cell Chem Biol. 2020 Mar 3. pii: S2451-9456(20)30067-2. doi:, 10.1016/j.chembiol.2020.02.003. PMID:32130941 doi:http://dx.doi.org/10.1016/j.chembiol.2020.02.003