9xs5

Factor inhibiting HIF-1 alpha in complex with Mn(II) and morin

spinqualitylabelsall models 9xs5, resolution 2.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9xs5 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.33Å Ligands: MN, MRI, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HIF1N_HUMAN Hydroxylates HIF-1 alpha at 'Asp-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Hydroxylates specific Asn residues within ankyrin repeat domains (ARD) of NFKB1, NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing proteins. Also hydroxylates Asp and His residues within ARDs of ANK1 and TNKS2, respectively. Negatively regulates NOTCH1 activity, accelerating myogenic differentiation. Positively regulates ASB4 activity, promoting vascular differentiation. Publication Abstract from PubMed Factor inhibiting HIF-1alpha (FIH) is a 2-oxoglutarate-dependent oxygenase that controls hypoxia signaling and metabolic homeostasis by hydroxylating HIF-1alpha. Although selective pharmacological inhibition of FIH represents an emerging therapeutic strategy for metabolic disorders, structurally diverse natural inhibitors remain largely unexplored. Here, we identified five natural FIH inhibitors spanning distinct phytochemical classes, including three flavonoids (wogonin, luteolin, morin), a coumarin (isofraxidin), and an anthraquinone (rhein). Co-crystal structures revealed that structurally diverse natural products converge on a common bidentate metal-chelation geometry within the FIH active site despite substantial differences in scaffold architecture. Among these inhibitors, wogonin most closely mimicked the orientation of the HIF-1alpha Asn803 side chain within the substrate-binding cleft, resulting in inhibitory potency comparable to that of the 2-oxoglutarate analog N-oxalylglycine. These findings establish the first structural framework for natural-product-based FIH inhibition and demonstrate that structurally distinct natural inhibitors adopt a conserved metal-chelation geometry within the FIH active site. This framework provides a basis for the future development of metabolically oriented FIH inhibitors. Structural Insights into Metal-Chelating Natural Inhibitors of Factor Inhibiting HIF-1alpha.,Akhsanitaqwim Y, Nakashima Y, Ikumi N, Morita H J Nat Prod. 2026 Jul 15. doi: 10.1021/acs.jnatprod.6c00734. PMID:42455177 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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