6ZBN
HIF Prolyl Hydroxylase 2 (PHD2/EGLN1) in complex with tert-butyl 6-(5-hydroxy-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-1-yl)nicotinate (IOX4)
Summary for 6ZBN
| Entry DOI | 10.2210/pdb6zbn/pdb |
| Descriptor | Egl nine homolog 1, ~{tert}-butyl 6-[5-oxidanyl-4-(1,2,3-triazol-1-yl)pyrazol-1-yl]pyridine-3-carboxylate, MANGANESE (II) ION, ... (5 entities in total) |
| Functional Keywords | inhibitor, complex, oxidoreductase, iox4, hif, phd2, hypoxia |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 6 |
| Total formula weight | 155181.41 |
| Authors | Figg Jr, W.D.,McDonough, M.A.,Nakashima, Y.,Schofield, C.J. (deposition date: 2020-06-08, release date: 2021-04-07, Last modification date: 2024-11-06) |
| Primary citation | Figg Jr., W.D.,McDonough, M.A.,Chowdhury, R.,Nakashima, Y.,Zhang, Z.,Holt-Martyn, J.P.,Krajnc, A.,Schofield, C.J. Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat. Chemmedchem, 16:2082-2088, 2021 Cited by PubMed Abstract: Human prolyl-hydroxylases (PHDs) are hypoxia-sensing 2-oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia-inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia-related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late-stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain-penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active-site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole π-π-stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking β2-β3, which are involved in dynamic substrate binding/product release. PubMed: 33792169DOI: 10.1002/cmdc.202100133 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.01 Å) |
Structure validation
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