Structural Insights into Metal-Chelating Natural Inhibitors of Factor Inhibiting HIF-1α.

Area of Science:

• Biochemistry
• Pharmacology
• Structural Biology

Background:

• Factor inhibiting HIF-1α (FIH) is a 2-oxoglutarate-dependent oxygenase crucial for regulating hypoxia signaling and metabolic homeostasis.
• FIH activity is modulated by hydroxylating HIF-1α, and its selective inhibition is a promising therapeutic strategy for metabolic disorders.
• Structurally diverse natural inhibitors of FIH are largely unexplored.

Purpose of the Study:

• To identify and structurally characterize natural compounds that inhibit FIH.
• To explore the potential of natural products as a basis for developing novel FIH inhibitors for metabolic diseases.

Main Methods:

• Phytochemical screening to identify natural FIH inhibitors.
• Co-crystal structure determination of FIH in complex with identified inhibitors.
• Biochemical assays to assess inhibitory potency.

Main Results:

• Five natural FIH inhibitors were identified across distinct phytochemical classes: three flavonoids (wogonin, luteolin, morin), a coumarin (isofraxidin), and an anthraquinone (rhein).
• Co-crystal structures revealed that these diverse natural products bind to the FIH active site via a conserved bidentate metal-chelation geometry.
• Wogonin exhibited potent FIH inhibition, closely mimicking the substrate's binding orientation.

Conclusions:

• This study provides the first structural framework for natural product-based FIH inhibition.
• Structurally distinct natural inhibitors converge on a conserved metal-chelation mechanism within the FIH active site.
• The findings pave the way for developing novel, metabolically oriented FIH inhibitors based on natural product scaffolds.