6AA4

Crystal structure of MTH1 in complex with alpha-mangostin (cocktail No. 9)

6AA4 の概要

• エントリーDOI: 10.2210/pdb6aa4/pdb
• 分子名称: 7,8-dihydro-8-oxoguanine triphosphatase, ZINC ION, 1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one, ... (5 entities in total)
• 機能のキーワード: hydrolase, nudt1, antitumor protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19622.90

構造登録者

Yokoyama, T.,Kitakami, R.,Mizuguchi, M. (登録日: 2018-07-17, 公開日: 2019-03-06, 最終更新日: 2024-10-23)

主引用文献

Yokoyama, T.,Kitakami, R.,Mizuguchi, M.
Discovery of a new class of MTH1 inhibitor by X-ray crystallographic screening.
Eur J Med Chem, 167:153-160, 2019

PubMed Abstract: MutT homologue 1 (MTH1) protects the nucleotide pool from oxidative stress by hydrolyzing oxidized nucleoside triphosphates and prevents their incorporation into DNA. Cancer cells are dependent on the MTH1 activity for survival due to the high-level of reactive oxygen species in cancer cells; therefore, MTH1 is considered to be a novel target for treatment of various cancers. Here, we show by X-ray crystallographic screening using an in-house cocktail library that α-mangostin, a natural xanthone from mangosteen pericarp, binds to the active site of MTH1. A subsequent inhibition assay revealed that 3-isomangostin, a cyclized derivative of α-mangostin, was the most potent MTH1 inhibitor, with an IC value of 0.052 μM. Detailed structural analyses of the MTH1-3-isomangostin complex showed the novel binding mode of 3-isomangostin. Our results demonstrate that X-ray crystallographic screening is useful for the lead discovery for MTH1, and suggest that 3-isomangostin would be an attractive chemical tool for the development of anticancer agents.

PubMed: 30771603
DOI: 10.1016/j.ejmech.2019.02.011

実験手法

X-RAY DIFFRACTION (1.9 Å)