6ux9

From Proteopedia

Crystal Structure Analysis of PIP4K2A

PDB ID 6ux9

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Structural highlights

6ux9 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 1.71Å
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

Due to their role in many important signaling pathways, phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive targets for the development of experimental therapeutics for cancer, metabolic, and immunological disorders. Recent efforts to develop small molecule inhibitors for these lipid kinases resulted in compounds with low- to sub-micromolar potencies. Here, we report the identification of CVM-05-002 using a high-throughput screen of PI5P4Kalpha against our in-house kinase inhibitor library. CVM-05-002 is a potent and selective inhibitor of PI5P4Ks, and a 1.7 A X-ray structure reveals its binding interactions in the ATP-binding pocket. Further investigation of the structure-activity relationship led to the development of compound 13, replacing the rhodanine-like moiety present in CVM-05-002 with an indole, a potent pan-PI5P4K inhibitor with excellent kinome-wide selectivity. Finally, we employed isothermal cellular thermal shift assays (CETSAs) to demonstrate the effective cellular target engagement of PI5P4Kalpha and -beta by the inhibitors in HEK 293T cells.

Discovery and Structure-Activity Relationship Study of (Z)-5-Methylenethiazolidin-4-one Derivatives as Potent and Selective Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors.,Manz TD, Sivakumaren SC, Ferguson FM, Zhang T, Yasgar A, Seo HS, Ficarro SB, Card JD, Shim H, Miduturu CV, Simeonov A, Shen M, Marto JA, Dhe-Paganon S, Hall MD, Cantley LC, Gray NS J Med Chem. 2020 May 14;63(9):4880-4895. doi: 10.1021/acs.jmedchem.0c00227. Epub , 2020 Apr 27. PMID:32298120^[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
↑ Manz TD, Sivakumaren SC, Ferguson FM, Zhang T, Yasgar A, Seo HS, Ficarro SB, Card JD, Shim H, Miduturu CV, Simeonov A, Shen M, Marto JA, Dhe-Paganon S, Hall MD, Cantley LC, Gray NS. Discovery and Structure-Activity Relationship Study of (Z)-5-Methylenethiazolidin-4-one Derivatives as Potent and Selective Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors. J Med Chem. 2020 May 14;63(9):4880-4895. doi: 10.1021/acs.jmedchem.0c00227. Epub , 2020 Apr 27. PMID:32298120 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00227