8II0

FACTOR INHIBITING HIF-1 ALPHA in complex with (5-(3-(3-chlorophenyl)isoxazol-5-yl)-3-hydroxypicolinoyl)glycine

8II0 の概要

• エントリーDOI: 10.2210/pdb8ii0/pdb
• 分子名称: Hypoxia-inducible factor 1-alpha inhibitor, 2-[[5-[3-(3-chlorophenyl)-1,2-oxazol-5-yl]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic acid, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: factor-inhibiting hypoxia-inducible factor, fih, 2og dependent dioxygenase, oxidoreductase
• 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: 41720.13

構造登録者

Nakashima, Y.,Corner, T.,Zhang, X.,Schofield, C.J. (登録日: 2023-02-24, 公開日: 2024-02-28, 最終更新日: 2024-10-09)

主引用文献

Wu, Y.,Chen, Y.,Corner, T.P.,Nakashima, Y.,Salah, E.,Li, Z.,Zhang, L.,Yang, L.,Tumber, A.,Sun, Z.,Wen, Y.,Zhong, A.,Yang, F.,Li, X.,Zhang, Z.,Schofield, C.J.,Zhang, X.
A Small-Molecule Inhibitor of Factor Inhibiting HIF Binding to a Tyrosine-Flip Pocket for the Treatment of Obesity.
Angew.Chem.Int.Ed.Engl., 63:e202410438-e202410438, 2024

PubMed Abstract: In animals, limiting oxygen upregulates the hypoxia-inducible factor (HIF) and promotes a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF function by reducing its interaction with histone acetyl transferases. HIF levels are negatively regulated by the HIF prolyl hydroxylases (PHDs) which, like FIH, are 2-oxoglutarate (2OG) oxygenases. Genetic loss of FIH promotes both glycolysis and aerobic metabolism. FIH has multiple non-HIF substrates making it challenging to connect its biochemistry with physiology. A structure-mechanism guided approach identified a highly potent in vivo active FIH inhibitor, ZG-2291, the binding of which promotes a conformational flip of a catalytically important tyrosine, enabling the selective inhibition of FIH over other Jumonji C subfamily 2OG oxygenases. Consistent with genetic studies, ZG-2291 promotes thermogenesis and ameliorates symptoms of obesity and metabolic dysfunction in ob/ob mice. The results reveal ZG-2291 as a useful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treatment.

PubMed: 38923188
DOI: 10.1002/anie.202410438

実験手法

X-RAY DIFFRACTION (2.04 Å)