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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
ZHA MANWU; GUO QING; ZHANG YICHUN; Yu B(俞飚); OU YING; ZHONG CHEN; Ding JP(丁建平)
2008
发表期刊J. Mol. Biol.
ISSN0022-2836
卷号379期号:3页码:568-578
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.
学科领域生命有机化学
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
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收录类别SCI
语种英语
WOS记录号WOS:000256586500015
引用统计
被引频次:17[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.sioc.ac.cn/handle/331003/19077
专题生命有机化学国家重点实验室
通讯作者ZHONG CHEN; Ding JP(丁建平)
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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.
APA ZHA MANWU.,GUO QING.,ZHANG YICHUN.,俞飚.,OU YING.,...&丁建平.(2008).Molecular mechanism of ADP-ribose hydrolysis by human NUDT5 from structural and kinetic studies.J. Mol. Biol.,379(3),568-578.
MLA ZHA MANWU,et al."Molecular mechanism of ADP-ribose hydrolysis by human NUDT5 from structural and kinetic studies".J. Mol. Biol. 379.3(2008):568-578.
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