View source for 9fsn


==FIH in complex with Enarodustat crystal structure at 2.2A==
<StructureSection load='9fsn' size='340' side='right'caption='[[9fsn]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9fsn]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9FSN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FSN FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IF7:2-[[7-oxidanylidene-5-(2-phenylethyl)-3~{H}-[1,2,4]triazolo[1,5-a]pyridin-8-yl]carbonylamino]ethanoic+acid'>A1IF7</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9fsn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fsn OCA], [https://pdbe.org/9fsn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fsn RCSB], [https://www.ebi.ac.uk/pdbsum/9fsn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fsn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/HIF1N_HUMAN HIF1N_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.<ref>PMID:12080085</ref> <ref>PMID:12042299</ref> <ref>PMID:17003112</ref> <ref>PMID:18299578</ref> <ref>PMID:19245366</ref> <ref>PMID:17573339</ref> <ref>PMID:21251231</ref> <ref>PMID:21177872</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Prolyl hydroxylase domain-containing proteins 1-3 (PHD1-3) are 2-oxoglutarate (2OG)-dependent oxygenases catalysing C-4 hydroxylation of prolyl residues in alpha-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF), modifications that promote HIF-alpha degradation via the ubiquitin-proteasome pathway. Pharmacological inhibition of the PHDs induces HIF-alpha stabilisation, so promoting HIF target gene transcription. PHD inhibitors are used to treat anaemia caused by chronic kidney disease (CKD) due to their ability to stimulate erythropoietin (EPO) production. We report studies on the effects of the approved PHD inhibitors Desidustat and Enarodustat, and the clinical candidate TP0463518, on activities of a representative set of isolated recombinant human 2OG oxygenases. The three molecules manifest selectivity for PHD inhibition over that of the other 2OG oxygenases evaluated. We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia-inducible factor-alpha (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1-3. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA-damage repair, and agrochemical resistance.

Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat.,Corner TP, Salah E, Tumber A, Kaur S, Nakashima Y, Allen MD, Schnaubelt LI, Fiorini G, Brewitz L, Schofield CJ ChemMedChem. 2024 Dec 16;19(24):e202400504. doi: 10.1002/cmdc.202400504. Epub , 2024 Nov 8. PMID:39291299<ref>PMID:39291299</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9fsn" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Allen MD]]
[[Category: Brewitz L]]
[[Category: Corner T]]
[[Category: Kaur S]]
[[Category: Schnaubelt LI]]
[[Category: Schofield CJ]]