View source for 9i4h


==Factor Inhibiting HIF (FIH) in complex with manganese and 3-Hydroxy-5-(3-(4-(hydroxymethyl)-3-nitrophenyl)isoxazol-5-yl)picolinoyl)glycine==
<StructureSection load='9i4h' size='340' side='right'caption='[[9i4h]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9i4h]] 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=9I4H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9I4H 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]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IZ5:2-[[5-[3-[4-(hydroxymethyl)-3-nitro-phenyl]-1,2-oxazol-5-yl]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic+acid'>A1IZ5</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=9i4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9i4h OCA], [https://pdbe.org/9i4h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9i4h RCSB], [https://www.ebi.ac.uk/pdbsum/9i4h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9i4h 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 ==
Factor inhibiting hypoxia-inducible factor (FIH) is a JmjC domain 2-oxoglutarate (2OG) and Fe(II)-dependent oxygenase that catalyzes protein hydroxylations, including of specific asparagines in the C-terminal transcriptional activation domains of hypoxia-inducible factor alpha (HIF-alpha) isoforms. FIH is of medicinal interest due to its ability to alter metabolism and modulate the course of the HIF-mediated hypoxic response. We report the development of a light-induced, lysine (Lys106)-targeting irreversible covalent inhibitor of FIH. The approach is complementary to optogenetic methods for regulation of transcription. The covalently reacting inhibitor NBA-ZG-2291 was the result of structure-guided modification of the reported active site binding FIH inhibitor ZG-2291 with an appropriately positioned o-nitrobenzyl alcohol (o-NBA) group. The results demonstrate that NBA-ZG-2291 forms a stable covalent bond in a light-dependent process with Lys106 of FIH, inactivating its hydroxylation activity and resulting in sustained upregulation of FIH-dependent HIF target genes. The light-controlled inhibitors targeting a lysine residue enable light and spatiotemporal control of FIH activity in a manner useful for dissecting the context-dependent physiological roles of FIH.

Light-Induced, Lysine-Targeting Irreversible Covalent Inhibition of the Human Oxygen Sensing Hydroxylase Factor Inhibiting HIF (FIH).,Wu Y, Li Z, Kaur S, Zhang Z, Yue J, Tumber A, Zhang H, Song Z, Yang P, Dong Y, Yang F, Li X, Schofield CJ, Zhang X J Am Chem Soc. 2025 May 9. doi: 10.1021/jacs.5c01935. PMID:40344676<ref>PMID:40344676</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9i4h" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Kaur S]]
[[Category: Schofield CJ]]
[[Category: Zhang XJ]]