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7Q5X

HIF PROLYL HYDROXYLASE 2 (PHD2/EGLN1) IN COMPLEX WITH 2-OXOGLUTARATE (2OG) AND HIF-2 ALPHA CODD (523-542)

Summary for 7Q5X
Entry DOI10.2210/pdb7q5x/pdb
DescriptorEgl nine homolog 1, Endothelial PAS domain-containing protein 1, MANGANESE (II) ION, ... (10 entities in total)
Functional Keywordsphd2, hif-2alpha, complex, 2og, oxidoreductase, hypoxia
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains2
Total formula weight29430.92
Authors
Figg Jr, W.D.,McDonough, M.A.,Chowdhury, R.,Nakashima, Y.,Schofield, C.J. (deposition date: 2021-11-04, release date: 2022-11-16, Last modification date: 2024-01-31)
Primary citationFigg Jr., W.D.,Fiorini, G.,Chowdhury, R.,Nakashima, Y.,Tumber, A.,McDonough, M.A.,Schofield, C.J.
Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2 alpha to prolyl hydroxylase domain 2.
Proteins, 91:1510-1524, 2023
Cited by
PubMed 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.
PubMed: 37449559
DOI: 10.1002/prot.26541
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.21 Å)
Structure validation

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