Structural basis of prolyl hydroxylase domain inhibition by Molidustat
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...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2021
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| _version_ | 1797088940597968896 |
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| author | Figg, WD McDonough, MA Chowdhury, R Nakashima, Y Zhang, Z Holt-Martyn, JP Krajnc, A Schofield, CJ |
| author_facet | Figg, WD McDonough, MA Chowdhury, R Nakashima, Y Zhang, Z Holt-Martyn, JP Krajnc, A Schofield, CJ |
| author_sort | Figg, WD |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:57:19Z |
| format | Journal article |
| id | oxford-uuid:afc1f48b-6d97-44b0-b8d0-07fc7fcc19ae |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:57:19Z |
| publishDate | 2021 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:afc1f48b-6d97-44b0-b8d0-07fc7fcc19ae2022-03-27T03:51:39ZStructural basis of prolyl hydroxylase domain inhibition by MolidustatJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:afc1f48b-6d97-44b0-b8d0-07fc7fcc19aeEnglishSymplectic ElementsWiley2021Figg, WDMcDonough, MAChowdhury, RNakashima, YZhang, ZHolt-Martyn, JPKrajnc, ASchofield, CJHuman 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. |
| spellingShingle | Figg, WD McDonough, MA Chowdhury, R Nakashima, Y Zhang, Z Holt-Martyn, JP Krajnc, A Schofield, CJ Structural basis of prolyl hydroxylase domain inhibition by Molidustat |
| title | Structural basis of prolyl hydroxylase domain inhibition by Molidustat |
| title_full | Structural basis of prolyl hydroxylase domain inhibition by Molidustat |
| title_fullStr | Structural basis of prolyl hydroxylase domain inhibition by Molidustat |
| title_full_unstemmed | Structural basis of prolyl hydroxylase domain inhibition by Molidustat |
| title_short | Structural basis of prolyl hydroxylase domain inhibition by Molidustat |
| title_sort | structural basis of prolyl hydroxylase domain inhibition by molidustat |
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