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Structural basis of prolyl hydroxylase domain inhibition by molidustat

DOI: 10.1002/cmdc.202100133 DOI Help

Authors: William D. Figg (University of Oxford) , Michael A. Mcdonough (University of Oxford) , Rasheduzzaman Chowdhury (University of Oxford; University of California, San Francisco) , Yu Nakashima (University of Oxford; University of Toyama) , Zhihong Zhang (University of Oxford) , James P. Holt‐martyn (University of Oxford) , Alen Krajnc (University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem , VOL 5

State: Published (Approved)
Published: April 2021
Diamond Proposal Number(s): 18069

Open Access Open Access

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.

Journal Keywords: oxygenases; anaemia; hypoxia-inducible factor-alpha (HIF); Molidustat; enzyme inhibition

Diamond Keywords: Anaemia

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I04-Macromolecular Crystallography

Added On: 19/04/2021 13:11


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)