6M8C
Crystal structure of the core catalytic domain of human inositol phosphate multikinase in complex with isorhamnetin
Summary for 6M8C
| Entry DOI | 10.2210/pdb6m8c/pdb |
| Descriptor | Inositol polyphosphate multikinase,Inositol polyphosphate multikinase, isorhamnetin (3 entities in total) |
| Functional Keywords | kinase, inositol, inositol polyphosphate, transferase, isorhamnetin, flavonoid, inhibitor, natural product |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 30144.17 |
| Authors | Wang, H.,Shears, S.B. (deposition date: 2018-08-21, release date: 2019-01-23, Last modification date: 2023-10-11) |
| Primary citation | Gu, C.,Stashko, M.A.,Puhl-Rubio, A.C.,Chakraborty, M.,Chakraborty, A.,Frye, S.V.,Pearce, K.H.,Wang, X.,Shears, S.B.,Wang, H. Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis. J. Med. Chem., 62:1443-1454, 2019 Cited by PubMed Abstract: 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 μM; 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. PubMed: 30624931DOI: 10.1021/acs.jmedchem.8b01593 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
Download full validation report
