View source for 9fs2


==Mutant S1538A of the dihydroorotase domain of human CAD protein bound to substrate==
<StructureSection load='9fs2' size='340' side='right'caption='[[9fs2]], [[Resolution|resolution]] 1.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9fs2]] 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=9FS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9FS2 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]] 1.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DOR:(4S)-2,6-DIOXOHEXAHYDROPYRIMIDINE-4-CARBOXYLIC+ACID'>DOR</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene>, <scene name='pdbligand=NCD:N-CARBAMOYL-L-ASPARTATE'>NCD</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=9fs2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9fs2 OCA], [https://pdbe.org/9fs2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9fs2 RCSB], [https://www.ebi.ac.uk/pdbsum/9fs2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9fs2 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 ==
CAD, the multi-enzymatic protein essential for initiating the de novo biosynthesis of pyrimidine nucleotides, forms large hexamers whose structure and function are not fully understood. Defects in CAD cause a severe neurometabolic disorder that is challenging to diagnose. We developed a cellular functional assay to identify defective CAD variants, and in this study, we characterized five pathogenic missense mutations in CAD's dihydroorotase (DHO) and aspartate transcarbamoylase (ATC) domains. All mutations impaired enzymatic activities, with two notably disrupting the formation of DHO dimers and ATC trimers. Combining crystal structures and AlphaFold predictions, we modeled the hexameric CAD complex, highlighting the central role of the DHO and ATC domains in its assembly. Our findings provide insight into CAD's stability, function, and organization, revealing that correct oligomerization of CAD into a supramolecular complex is required for its function in nucleotide synthesis and that mutations affecting this assembly are potentially pathogenic.

Disruption of CAD Oligomerization by Pathogenic Variants.,Del Cano-Ochoa F, Ramadane-Morchadi L, Eixeres L, Moreno-Morcillo M, Fernandez-Leiro R, Ramon-Maiques S J Mol Biol. 2024 Dec 1;436(23):168832. doi: 10.1016/j.jmb.2024.168832. Epub 2024 , Oct 22. PMID:39447673<ref>PMID:39447673</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9fs2" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ramon-Maiques S]]
[[Category: Del Cano-Ochoa F]]