6m89 | pdb_00006m89

Crystal structure of the core catalytic domain of human inositol phosphate multikinase in complex with quercetin

spinqualitylabelsall models 6m89, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6m89 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 1.85Å Ligands: QUE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function IPMK_HUMAN Inositol phosphate kinase with a broad substrate specificity. Has a preference for inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and inositol 1,3,4,6-tetrakisphosphate (Ins(1,3,4,6)P4). Publication Abstract from PubMed Dietary flavonoids inhibit certain protein kinases and phospholipid kinases by competing for their ATP-binding sites. These nucleotide pockets have structural elements that are well-conserved in two human small-molecule kinases, inositol hexakisphosphate kinase (IP6K) and inositol polyphosphate multikinase (IPMK), which synthesize multifunctional inositol phosphate cell signals. Herein, we demonstrate that both kinases are inhibited by quercetin and 16 related flavonoids; IP6K is the preferred target. Relative inhibitory activities were rationalized by X-ray analysis of kinase/flavonoid crystal structures; this detailed structure-activity analysis revealed hydrophobic and polar ligand/protein interactions, the degree of flexibility of key amino acid side chains, and the importance of water molecules. The seven most potent IP6K inhibitors were incubated with intact HCT116 cells at concentrations of 2.5 muM; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Our data can instruct on pharmacophore properties to assist the future development of inositol phosphate kinase inhibitors. Finally, we propose that dietary flavonoids may inhibit IP6K activity in cells that line the gastrointestinal tract. Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis.,Gu C, Stashko MA, Puhl-Rubio AC, Chakraborty M, Chakraborty A, Frye SV, Pearce KH, Wang X, Shears SB, Wang H J Med Chem. 2019 Feb 14;62(3):1443-1454. doi: 10.1021/acs.jmedchem.8b01593. Epub , 2019 Jan 25. PMID:30624931 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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