6M8C

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

6M8C の概要

• エントリーDOI: 10.2210/pdb6m8c/pdb
• 分子名称: Inositol polyphosphate multikinase,Inositol polyphosphate multikinase, isorhamnetin (3 entities in total)
• 機能のキーワード: kinase, inositol, inositol polyphosphate, transferase, isorhamnetin, flavonoid, inhibitor, natural product
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30144.17

構造登録者

Wang, H.,Shears, S.B. (登録日: 2018-08-21, 公開日: 2019-01-23, 最終更新日: 2023-10-11)

主引用文献

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

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: 30624931
DOI: 10.1021/acs.jmedchem.8b01593

実験手法

X-RAY DIFFRACTION (1.8 Å)