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A more recent version of this article appeared on August 6, 2004 Originally published In Press as doi:10.1074/jbc.M404298200 on June 9, 2004
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Papers In Press, published online ahead of print June 1, 2004
J. Biol. Chem, 10.1074/jbc.M404298200
Submitted on April 19, 2004
Revised on May 24, 2004
Accepted on June 1, 2004

Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity

Xiang Xu, Jingyue Zhao, Zhen Xu, Baozhen Peng, Qiuhua Huang, Eddy Arnold, and Jianping Ding

Key Laboratory of Proteomics, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031

Corresponding Author: jpding{at}sibs.ac.cn

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to a-ketoglutarate and regulation of the enzymatic activity of IDHs is crucial for their biological functions. Bacterial IDHs are reversibly regulated by phosphorylation of a strictly conserved serine residue at the active site. Eukaryotic NADP-dependent IDHs (NADP-IDHs) have been shown to have diverse important biological functions; however, their regulatory mechanism remains unclear. Structural studies of human cytosolic NADP-IDH (HcIDH) in complex with NADP and in complex with NADP, isocitrate, and Ca2+ reveal three biologically relevant conformational states of the enzyme that differ substantially in the structure of the active site and in the overall structure. A structural segment at the active site that forms a conserved a-helix in all known NADP-IDH structures assumes a loop conformation in the open, inactive form of HcIDH, a partially unraveled -helix in the semi-open, intermediate form, and an -helix in the closed, active form. The side chain of Asp279 of this segment occupies the isocitrate binding site and forms hydrogen bonds with Ser94 (the equivalent of the phosphorylation site in bacterial IDHs) in the inactive form and chelates the metal ion in the active form. The structural data led us to propose a novel self-regulatory mechanism for HcIDH that mimics the phosphorylation mechanism used by the bacterial homologs, consistent with biochemical and biological data. This mechanism might be applicable to other eukaryotic NADP-IDHs. The results also provide insights into the recognition and specificity of substrate and cofactor by eukaryotic NADP-IDHs.


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