6GK0

HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH CLASS III HISTONE DEACETYLASE INHIBITOR

6GK0 の概要

• エントリーDOI: 10.2210/pdb6gk0/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, (4S)-2,6-DIOXOHEXAHYDROPYRIMIDINE-4-CARBOXYLIC ACID, ... (10 entities in total)
• 機能のキーワード: dehydrogenase dhodh tumor-killing drug development, 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: 41975.04

構造登録者

Hakansson, M.,Ladds, M.J.G.W.,Walse, B.,Lain, S. (登録日: 2018-05-17, 公開日: 2019-11-27, 最終更新日: 2024-05-15)

主引用文献

Ladds, M.J.G.W.,Popova, G.,Pastor-Fernandez, A.,Kannan, S.,van Leeuwen, I.M.M.,Hakansson, M.,Walse, B.,Tholander, F.,Bhatia, R.,Verma, C.S.,Lane, D.P.,Lain, S.
Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology.
J.Biol.Chem., 295:17935-17949, 2020

PubMed Abstract: The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

PubMed: 32900849
DOI: 10.1074/jbc.RA119.012056

実験手法

X-RAY DIFFRACTION (1.85 Å)