8k73 | pdb_00008k73
Factor-inhibiting hypoxia-inducible factor in complex with Zn(II) and 2-(3-hydroxy-2-((1-(phenylsulfonyl)pyrrolidine-3-carbonyl)imino)-2,3-dihydrothiazol-4-yl)acetic acid
Structural highlights
FunctionHIF1N_HUMAN Hydroxylates HIF-1 alpha at 'Asp-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Hydroxylates specific Asn residues within ankyrin repeat domains (ARD) of NFKB1, NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing proteins. Also hydroxylates Asp and His residues within ARDs of ANK1 and TNKS2, respectively. Negatively regulates NOTCH1 activity, accelerating myogenic differentiation. Positively regulates ASB4 activity, promoting vascular differentiation.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedThe human 2-oxoglutarate (2OG)- and Fe(ii)-dependent oxygenases factor inhibiting hypoxia-inducible factor-alpha (FIH) and HIF-alpha prolyl residue hydroxylases 1-3 (PHD1-3) regulate the response to hypoxia in humans via catalysing hydroxylation of the alpha-subunits of the hypoxia-inducible factors (HIFs). Small-molecule PHD inhibitors are used for anaemia treatment; by contrast, few selective inhibitors of FIH have been reported, despite their potential to regulate the hypoxic response, either alone or in combination with PHD inhibition. We report molecular, biophysical, and cellular evidence that the N-hydroxythiazole scaffold, reported to inhibit PHD2, is a useful broad spectrum 2OG oxygenase inhibitor scaffold, the inhibition potential of which can be tuned to achieve selective FIH inhibition. Structure-guided optimisation resulted in the discovery of N-hydroxythiazole derivatives that manifest substantially improved selectivity for FIH inhibition over PHD2 and other 2OG oxygenases, including Jumonji-C domain-containing protein 5 ( approximately 25-fold), aspartate/asparagine-beta-hydroxylase (>100-fold) and histone N(epsilon)-lysine demethylase 4A (>300-fold). The optimised N-hydroxythiazole-based FIH inhibitors modulate the expression of FIH-dependent HIF target genes and, consistent with reports that FIH regulates cellular metabolism, suppressed lipid accumulation in adipocytes. Crystallographic studies reveal that the N-hydroxythiazole derivatives compete with both 2OG and the substrate for binding to the FIH active site. Derivatisation of the N-hydroxythiazole scaffold has the potential to afford selective inhibitors for 2OG oxygenases other than FIH. Structure-guided optimisation of N-hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-alpha.,Corner TP, Teo RZR, Wu Y, Salah E, Nakashima Y, Fiorini G, Tumber A, Brasnett A, Holt-Martyn JP, Figg WD Jr, Zhang X, Brewitz L, Schofield CJ Chem Sci. 2023 Oct 27;14(43):12098-12120. doi: 10.1039/d3sc04253g. eCollection , 2023 Nov 8. PMID:37969593[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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