7Q5X
HIF PROLYL HYDROXYLASE 2 (PHD2/EGLN1) IN COMPLEX WITH 2-OXOGLUTARATE (2OG) AND HIF-2 ALPHA CODD (523-542)
Summary for 7Q5X
| Entry DOI | 10.2210/pdb7q5x/pdb |
| Descriptor | Egl nine homolog 1, Endothelial PAS domain-containing protein 1, MANGANESE (II) ION, ... (10 entities in total) |
| Functional Keywords | phd2, hif-2alpha, complex, 2og, oxidoreductase, hypoxia |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 29430.92 |
| 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: 2024-11-13) |
| Primary citation | Figg 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: 37449559DOI: 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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