4C6O

Crystal structure of the dihydroorotase domain of human CAD C1613S mutant in apo-form at pH 6.0

4C6O の概要

• エントリーDOI: 10.2210/pdb4c6o/pdb
• 関連するPDBエントリー: 4C6B 4C6C 4C6D 4C6E 4C6F 4C6I 4C6J 4C6K 4C6L 4C6M 4C6N 4C6P 4C6Q
• 分子名称: CAD PROTEIN, ZINC ION, FORMIC ACID, ... (4 entities in total)
• 機能のキーワード: hydrolase, de novo pyrimidine biosynthesis, amidohydrolase superfamily, metalloenzyme, zinc binding, histidinate anion
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm: P27708
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43214.87

構造登録者

Ramon-Maiques, S.,Lallous, N.,Grande-Garcia, A. (登録日: 2013-09-18, 公開日: 2014-02-05, 最終更新日: 2023-12-20)

主引用文献

Grande-Garcia, A.,Lallous, N.,Diaz-Tejada, C.,Ramon-Maiques, S.
Structure, Functional Characterization and Evolution of the Dihydroorotase Domain of Human Cad.
Structure, 22:185-, 2014

PubMed Abstract: 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 ∼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.

PubMed: 24332717
DOI: 10.1016/J.STR.2013.10.016

実験手法

X-RAY DIFFRACTION (1.65 Å)