ORCID Profile
0000-0003-2141-5988
Current Organisation
University of Oxford
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Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7SC02103H
Abstract: Four compounds in clinical trials for anaemia treatment are potent inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs), but differ in potency and how they interact with HIF at the PHD active site.
Publisher: Springer Science and Business Media LLC
Date: 17-08-2020
Publisher: Springer Science and Business Media LLC
Date: 26-08-2016
DOI: 10.1038/NCOMMS12673
Abstract: The response to hypoxia in animals involves the expression of multiple genes regulated by the αβ-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFα isoforms, as catalysed by prolyl hydroxylases (PHD 1–3). Prolyl hydroxylation promotes binding of HIFα to the von Hippel–Lindau protein (VHL)–elongin B/C complex, thus signalling for proteosomal degradation of HIFα. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors.
Publisher: Wiley
Date: 21-03-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8SC00286J
Abstract: Tight, non-active site binding cyclic peptides are promising affinity reagents for studying proteins and their interactions.
Publisher: Wiley
Date: 26-09-2018
Abstract: In animals, the response to chronic hypoxia is mediated by upregulation of the α,β-heterodimeric hypoxia-inducible factors (HIFs). Levels of HIFα isoforms, but not HIFβ, are regulated by their post-translational modification as catalysed by prolyl hydroxylase domain enzymes (PHDs). Different roles for the human HIF-1/2α isoforms and their two oxygen-dependent degradation domains (ODDs) are proposed. We report kinetic and NMR analyses of the ODD selectivity of the catalytic domain of wild-type PHD2 (which is conserved in nearly all animals) and clinically observed variants. Studies using Ala scanning and "hybrid" ODD peptides imply that the relatively rigid conformation of the (hydroxylated) proline plays an important role in ODD binding. They also reveal differential roles in binding for the residues on the N- and C-terminal sides of the substrate proline. The overall results indicate how the PHDs achieve selectivity for HIFα ODDs and might be of use in identifying substrate-selective PHD inhibitors.
Publisher: American Chemical Society (ACS)
Date: 09-07-2019
DOI: 10.1021/ACSCHEMBIO.9B00289
Abstract: Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are "epigenetic eraser" enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A)
Publisher: American Chemical Society (ACS)
Date: 17-08-2020
DOI: 10.1021/JACS.0C07877
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8CC00387D
Abstract: The binding of prolyl-hydroxylated HIF-α to PHD2 is hindered by prior 2OG binding likely, leading to the inhibition of HIF-α degradation under limiting 2OG conditions.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Martine I. Abboud.