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学科主题: 生命有机化学
题名: Molecular mechanism of ADP-ribose hydrolysis by human NUDT5 from structural and kinetic studies
其他题名: 从结构和动力学研究解释人NUDT5对ADP核糖水解的分子机制
作者: ZHA MANWU ; GUO QING ; ZHANG YICHUN ; Yu B(俞飚) ; OU YING ; ZHONG CHEN ; Ding JP(丁建平)
通讯作者: ZHONG CHEN ; 丁建平
刊名: J. Mol. Biol.
发表日期: 2008
卷: 379, 期:3, 页:568-578
收录类别: SCI
部门归属: 中科院上海生命科学研究院生物化学与细胞生物学研究所; 中科院上海有机所
英文摘要: Human NUDT5 (hNUDT5) is an ADP-ribose (ADPR) pyrophosphatase (ADPRase) that plays important roles in controlling the intracellular levels of ADPR and preventing non-enzymatic ADP-ribosylation of proteins by hydrolyzing ADPR to AMP and ribose 5'-phosphate. We report the crystal structure of hNUDT5 in complex with a non-hydrolyzable ADPR analogue, alpha,beta-methyleneadenosine diphosphoribose, and three Mg2+ ions representing the transition state of the enzyme during catalysis. Analysis of this structure and comparison with previously reported hNUDT5 structures identify key residues involved in substrate binding and catalysis. In the transition-state structure, three metal ions are bound at the active site and are coordinated by surrounding residues and water molecules. A conserved water molecule is at an ideal position for nucleophilic attack on the a-phosphate of ADPR. The side chain of Glu166 on loop L9 changes its conformation to interact with the conserved water molecule compared with that in the substrate-bound structure and appears to function as a catalytic base. Mutagenesis and kinetic studies show that Trp28 and Trp46 are important for the substrate binding; Arg51 is involved in both the substrate binding and the catalysis; and Glu112 and Glu116 of the Nudix motif, Glu166 on loop L9, and Arg111 are critical for the catalysis. The structural and biochemical data together reveal the molecular basis of the catalytic mechanism of ADPR hydrolysis by hNUDT5. Specifically, Glu166 functions as a catalytic base to deprotonate a conserved water molecule that acts as a nucleophile to attack the alpha-phosphate of ADPR, and three Mg2+ ions are involved in the activation of the nucleophile and the binding of the substrate. Structural comparison of different ADPRases also suggests that most dimeric ADPRases may share a similar catalytic mechanism of ADPR hydrolysis. (c) 2008 Elsevier Ltd. All rights reserved.
语种: 英语
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WOS记录号: WOS:000256586500015
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内容类型: 期刊论文
URI标识: http://ir.sioc.ac.cn/handle/331003/19077
Appears in Collections:生命有机化学国家重点实验室_期刊论文

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Recommended Citation:
ZHA MANWU,GUO QING,ZHANG YICHUN,et al. Molecular mechanism of ADP-ribose hydrolysis by human NUDT5 from structural and kinetic studies[J]. J. Mol. Biol.,2008,379(3):568-578.
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