9fs1

Mutant S1538L of the dihydroorotase domain of human CAD protein bound to carbamoyl aspartate

spinqualitylabelsall models 9fs1, resolution 1.21Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9fs1 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.21Å Ligands: FMT, KCX, NCD, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PYR1_HUMAN This protein is a "fusion" protein encoding four enzymatic activities of the pyrimidine pathway (GATase, CPSase, ATCase and DHOase). 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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