View source for 9jtx


==Factor inhibiting HIF-1 alpha in complex with Zn(II) and 2-(4-hydroxy-2-oxo-1-(thiazol-4-ylmethoxy)-1,2-dihydroquinoline-3-carboxamido)-2-methylpropanoic acid==
<StructureSection load='9jtx' size='340' side='right'caption='[[9jtx]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9jtx]] 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=9JTX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9JTX 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]] 2.08&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L4V:2-methyl-2-[[4-oxidanyl-2-oxidanylidene-1-(1,3-thiazol-4-ylmethoxy)quinolin-3-yl]carbonylamino]propanoic+acid'>A1L4V</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=9jtx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9jtx OCA], [https://pdbe.org/9jtx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9jtx RCSB], [https://www.ebi.ac.uk/pdbsum/9jtx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9jtx 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 ==
The 2-oxoglutarate (2OG)/Fe(II)-dependent gamma-butyrobetaine hydroxylase (BBOX) catalyzes the final step in l-carnitine biosynthesis, i.e., stereoselective C-3 oxidation of gamma-butyrobetaine (GBB). BBOX inhibition is a validated clinical strategy to modulate l-carnitine levels and to enhance cardiovascular efficiency. Reported BBOX inhibitors, including the clinically used cardioprotective agent Mildronate, manifest moderate inhibitory activity in vitro, limited selectivity, and/or unfavorable physicochemical properties, indicating a need for improved BBOX inhibitors. We report that the clinically used hypoxia-inducible factor-alpha prolyl residue hydroxylase (PHD) inhibitors Desidustat, Enarodustat, and Vadadustat efficiently inhibit isolated recombinant BBOX, suggesting that BBOX inhibition by clinically used PHD inhibitors should be considered as a possible off-target effect. Structure-activity relationship studies on the Desidustat scaffold enabled development of potent BBOX inhibitors that manifest high levels of selectivity for BBOX inhibition over representative human 2OG oxygenases, including PHD2. The Desidustat derivatives will help to enable investigations into the biological roles of l-carnitine and the therapeutic potential of BBOX inhibition.

Derivatives of the Clinically Used HIF Prolyl Hydroxylase Inhibitor Desidustat Are Efficient Inhibitors of Human gamma-Butyrobetaine Hydroxylase.,Corner TP, Tumber A, Salah E, Jabbary M, Nakashima Y, Schnaubelt LI, Basak S, Alshref FM, Brewitz L, Schofield CJ J Med Chem. 2025 Apr 22. doi: 10.1021/acs.jmedchem.5c00586. PMID:40263713<ref>PMID:40263713</ref>

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