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4c6f

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Crystal structure of the dihydroorotase domain of human CAD bound to substrate at pH 6.5

Structural highlights

4c6f 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 1.261Å
Ligands:	, , , ,
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

Upregulation of CAD, the multifunctional protein that initiates and controls the de novo biosynthesis of pyrimidines in animals, is essential for cell proliferation. Deciphering the architecture and functioning of CAD is of interest for its potential usage as an antitumoral target. However, there is no detailed structural information about CAD other than that it self-assembles into hexamers of approximately 1.5 MDa. Here we report the crystal structure and functional characterization of the dihydroorotase domain of human CAD. Contradicting all assumptions, the structure reveals an active site enclosed by a flexible loop with two Zn2+ ions bridged by a carboxylated lysine and a third Zn coordinating a rare histidinate ion. Site-directed mutagenesis and functional assays prove the involvement of the Zn and flexible loop in catalysis. Comparison with homologous bacterial enzymes supports a reclassification of the DHOase family and provides strong evidence against current models of the architecture of CAD.

Structure, Functional Characterization, and Evolution of the Dihydroorotase Domain of Human CAD.,Grande-Garcia A, Lallous N, Diaz-Tejada C, Ramon-Maiques S Structure. 2013 Dec 10. pii: S0969-2126(13)00428-0. doi:, 10.1016/j.str.2013.10.016. PMID:24332717^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Grande-Garcia A, Lallous N, Diaz-Tejada C, Ramon-Maiques S. Structure, Functional Characterization, and Evolution of the Dihydroorotase Domain of Human CAD. Structure. 2013 Dec 10. pii: S0969-2126(13)00428-0. doi:, 10.1016/j.str.2013.10.016. PMID:24332717 doi:http://dx.doi.org/10.1016/j.str.2013.10.016