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

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.

Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation

“…The HIF gene family consists of three isoforms, namely HIF-1, HIF-2, and HIF-3 [ 11 , 12 ]. Every isoform is composed of a dimeric configuration comprising an alpha (α) subunit sensitive to oxygen and a beta (β) subunit insensitive to oxygen.…”

“…Every isoform is composed of a dimeric configuration comprising an alpha (α) subunit sensitive to oxygen and a beta (β) subunit insensitive to oxygen. β subunits are collectively referred as aryl hydrocarbon receptor nuclear translocator (ARNT) [12] (Figure 1). All HIF members contain a bHLH motif and two PAS domains (PAS-A and PAS-B).…”