7qie

Crystal Structure of Phosphatidylinositol 5-Phosphate 4-Kinase (PI5P4K2C) bound to an allosteric inhibitor

spinqualitylabelsall models 7qie, resolution 2.39Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7qie is a 4 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 2.39Å Ligands: DVF Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PI42C_HUMAN May play an important role in the production of Phosphatidylinositol bisphosphate (PIP2), in the endoplasmic reticulum. Publication Abstract from PubMed Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are emerging as attractive therapeutic targets in diseases, such as cancer, immunological disorders, and neurodegeneration, owing to their central role in regulating cell signaling pathways that are either dysfunctional or can be modulated to promote cell survival. Different modes of binding may enhance inhibitor selectivity and reduce off-target effects in cells. Here, we describe efforts to improve the physicochemical properties of the selective PI5P4Kgamma inhibitor, NIH-12848 (1). These improvements enabled the demonstration that this chemotype engages PI5P4Kgamma in intact cells and that compounds from this series do not inhibit PI5P4Kalpha or PI5P4Kbeta. Furthermore, the first X-ray structure of PI5P4Kgamma bound to an inhibitor has been determined with this chemotype, confirming an allosteric binding mode. An exemplar from this chemical series adopted two distinct modes of inhibition, including through binding to a putative lipid interaction site which is 18 A from the ATP pocket. Development of Selective Phosphatidylinositol 5-Phosphate 4-Kinase gamma Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode.,Boffey HK, Rooney TPC, Willems HMG, Edwards S, Green C, Howard T, Ogg D, Romero T, Scott DE, Winpenny D, Duce J, Skidmore J, Clarke JH, Andrews SP J Med Chem. 2022 Feb 24;65(4):3359-3370. doi: 10.1021/acs.jmedchem.1c01819. Epub , 2022 Feb 11. PMID:35148092 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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