Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2

William D. Figg, Giorgia Fiorini, Rasheduzzaman Chowdhury, Yu Nakashima, Anthony Tumber, Michael A. McDonough, Christopher J. Schofield*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The hypoxia-inducible factor (HIF) prolyl-hydroxylases (human PHD1-3) catalyze prolyl hydroxylation in oxygen-dependent degradation (ODD) domains of HIFα isoforms, modifications that signal for HIFα proteasomal degradation in an oxygen-dependent manner. PHD inhibitors are used for treatment of anemia in kidney disease. Increased erythropoietin (EPO) in patients with familial/idiopathic erythrocytosis and pulmonary hypertension is associated with mutations in EGLN1 (PHD2) and EPAS1 (HIF2α); a drug inhibiting HIF2α activity is used for clear cell renal cell carcinoma (ccRCC) treatment. We report crystal structures of PHD2 complexed with the C-terminal HIF2α-ODD in the presence of its 2-oxoglutarate cosubstrate or N-oxalylglycine inhibitor. Combined with the reported PHD2.HIFα-ODD structures and biochemical studies, the results inform on the different PHD.HIFα-ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform-selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment.

Original languageEnglish
Pages (from-to)1510-1524
Number of pages15
JournalProteins: Structure, Function and Bioinformatics
Volume91
Issue number11
DOIs
StatePublished - Nov 2023
Externally publishedYes

Keywords

  • Belzutifan
  • Trichoplax adhaerens and Pseudomonas putida prolyl hydroxylase domain (TaPHD and PPHD)
  • clear cell renal cell carcinoma
  • erythropoiesis
  • hypoxia-inducible factor isoform 2-alpha (HIF2α or EPAS1)
  • prolyl hydroxylase domain (PHD or EGLN)
  • α-ketoglutarate/2-oxoglutarate oxygenase

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