9I4H

Factor Inhibiting HIF (FIH) in complex with manganese and 3-Hydroxy-5-(3-(4-(hydroxymethyl)-3-nitrophenyl)isoxazol-5-yl)picolinoyl)glycine

これはPDB形式変換不可エントリーです。

9I4H の概要

• エントリーDOI: 10.2210/pdb9i4h/pdb
• 分子名称: Hypoxia-inducible factor 1-alpha inhibitor, MANGANESE (II) ION, N-[(5P)-3-hydroxy-5-{(3P)-3-[4-(hydroxymethyl)-3-nitrophenyl]-1,2-oxazol-5-yl}pyridine-2-carbonyl]glycine, ... (4 entities in total)
• 機能のキーワード: hypoxia-inducible factor 1-alpha inhibitor, factor inhibiting hif (fih), 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: 40884.62

構造登録者

Kaur, S.,Zhang, X.J.,Schofield, C.J. (登録日: 2025-01-24, 公開日: 2025-05-21, 最終更新日: 2026-04-15)

主引用文献

Wu, Y.,Li, Z.,Kaur, S.,Zhang, Z.,Yue, J.,Tumber, A.,Zhang, H.,Song, Z.,Yang, P.,Dong, Y.,Yang, F.,Li, X.,Schofield, C.J.,Zhang, X.
Light-Induced, Lysine-Targeting Irreversible Covalent Inhibition of the Human Oxygen Sensing Hydroxylase Factor Inhibiting HIF (FIH).
J.Am.Chem.Soc., 147:17871-17879, 2025

PubMed Abstract: Factor inhibiting hypoxia-inducible factor (FIH) is a JmjC domain 2-oxoglutarate (2OG) and Fe(II)-dependent oxygenase that catalyzes protein hydroxylations, including of specific asparagines in the -terminal transcriptional activation domains of hypoxia-inducible factor alpha (HIF-α) isoforms. FIH is of medicinal interest due to its ability to alter metabolism and modulate the course of the HIF-mediated hypoxic response. We report the development of a light-induced, lysine (Lys106)-targeting irreversible covalent inhibitor of FIH. The approach is complementary to optogenetic methods for regulation of transcription. The covalently reacting inhibitor was the result of structure-guided modification of the reported active site binding FIH inhibitor with an appropriately positioned -nitrobenzyl alcohol (-NBA) group. The results demonstrate that forms a stable covalent bond in a light-dependent process with Lys106 of FIH, inactivating its hydroxylation activity and resulting in sustained upregulation of FIH-dependent HIF target genes. The light-controlled inhibitors targeting a lysine residue enable light and spatiotemporal control of FIH activity in a manner useful for dissecting the context-dependent physiological roles of FIH.

PubMed: 40344676
DOI: 10.1021/jacs.5c01935

実験手法

X-RAY DIFFRACTION (2.3 Å)