View source for 9wic


==Crystal structure of the human dihydroorotase domain complexed with 5-aminoorotic acid reveals the loop in binding mode==
<StructureSection load='9wic' size='340' side='right'caption='[[9wic]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9wic]] 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=9WIC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WIC 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]] 1.83&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</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=9wic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9wic OCA], [https://pdbe.org/9wic PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9wic RCSB], [https://www.ebi.ac.uk/pdbsum/9wic PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9wic ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PYR1_HUMAN PYR1_HUMAN] This protein is a "fusion" protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Dihydroorotase (DHOase) catalyzes the reversible conversion of N-carbamoyl-L-aspartate to dihydroorotate in de novo pyrimidine biosynthesis. In humans, DHOase (huDHOase) is part of the CAD enzyme complex and contains a flexible loop that alternates between loop-in and loop-out conformations. Here, we identify 5-aminoorotic acid (5-AOA), previously known as a dihydroorotate dehydrogenase inhibitor, as a potent huDHOase inhibitor. Enzyme assays showed strong inhibition by 5-AOA (IC(50) = 9.87 muM) compared with weaker inhibition by 5-fluoroorotic acid (5-FOA; IC(50) = 191.59 muM). To elucidate the mechanism, we determined the crystal structures of huDHOase bound to 5-AOA (1.83 A; PDB ID: 9WIC) and to 5-FOA (1.55 A; PDB ID: 9WIN) for direct comparison. Structural analysis revealed distinct binding modes: 5-AOA bound in the loop-in conformation, forming extensive stabilizing interactions, whereas 5-FOA bound in the loop-out state with fewer contacts. Consistently, the T1562A mutation decreased the binding affinity of 5-AOA from 18.6 muM to 53.4 muM, an approximately threefold reduction, confirming the role of the loop in inhibitor recognition. These findings establish 5-AOA as a dual inhibitor in pyrimidine biosynthesis and highlight a loop-in binding mechanism for huDHOase inhibition.

Structural basis of potent inhibition of the human CAD dihydroorotase domain by 5-aminoorotic acid.,Huang YH, Huang TY, Wang MC, Huang CY Biochem Biophys Res Commun. 2025 Nov 1;787:152804. doi: , 10.1016/j.bbrc.2025.152804. Epub 2025 Oct 13. PMID:41101239<ref>PMID:41101239</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9wic" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Huang CY]]
[[Category: Huang HY]]
[[Category: Wang MC]]