9I4H
Factor Inhibiting HIF (FIH) in complex with manganese and 3-Hydroxy-5-(3-(4-(hydroxymethyl)-3-nitrophenyl)isoxazol-5-yl)picolinoyl)glycine
This is a non-PDB format compatible entry.
Summary for 9I4H
| Entry DOI | 10.2210/pdb9i4h/pdb |
| Descriptor | Hypoxia-inducible factor 1-alpha inhibitor, MANGANESE (II) ION, 2-[[5-[3-[4-(hydroxymethyl)-3-nitro-phenyl]-1,2-oxazol-5-yl]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic acid, ... (4 entities in total) |
| Functional Keywords | hypoxia-inducible factor 1-alpha inhibitor, factor inhibiting hif (fih), oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 40884.62 |
| Authors | |
| Primary citation | 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., 2025 Cited by 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: 40344676DOI: 10.1021/jacs.5c01935 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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