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

Proteins. 2023 Nov;91(11):1510-1524. doi: 10.1002/prot.26541. Epub 2023 Jul 14.


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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Renal Cell* / drug therapy
  • Carcinoma, Renal Cell* / genetics
  • Humans
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor-Proline Dioxygenases / chemistry
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Kidney Neoplasms* / drug therapy
  • Kidney Neoplasms* / genetics
  • Oxygen / metabolism
  • Procollagen-Proline Dioxygenase / chemistry
  • Procollagen-Proline Dioxygenase / genetics
  • Procollagen-Proline Dioxygenase / metabolism
  • Prolyl Hydroxylases
  • Protein Isoforms


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Oxygen
  • Procollagen-Proline Dioxygenase
  • Prolyl Hydroxylases
  • Protein Isoforms
  • endothelial PAS domain-containing protein 1