6ZBO

HIF Prolyl Hydroxylase 2 (PHD2/EGLN1) in Complex with 1-(6-morpholinopyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-ol (Molidustat)

Summary for 6ZBO

• Entry DOI: 10.2210/pdb6zbo/pdb
• Descriptor: Egl nine homolog 1, MANGANESE (II) ION, 2-(6-morpholin-4-ylpyrimidin-4-yl)-4-(1,2,3-triazol-1-yl)pyrazol-3-ol, ... (5 entities in total)
• Functional Keywords: phd2, inhibitor, complex, molidustat, oxidoreductase, hif
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 155466.07

Authors

Figg Jr, W.D.,McDonough, M.A.,Nakashima, Y.,Holt-Martyn, J.P.,Schofield, C.J. (deposition date: 2020-06-08, release date: 2021-04-07, Last modification date: 2024-01-24)

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

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: 33792169
DOI: 10.1002/cmdc.202100133

Experimental method

X-RAY DIFFRACTION (1.79 Å)