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Dynamic Conformations of the CD38-Mediated NAD Cyclization Captured in a Single Crystal
Zhang, HongMin1; Graeff, Richard2; Chen, Zhe3; Zhang, LiangRen3; Zhang, LiHe3; Lee, HonCheung1; Hao, Quan1
关键词Cd38 Cyclization Hydrolysis Cadpr Nad Analogue
刊名JOURNAL OF MOLECULAR BIOLOGY
2011-01-28
DOI10.1016/j.jmb.2010.11.044
405期:4页:1070-1078
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biochemistry & Molecular Biology
研究领域[WOS]Biochemistry & Molecular Biology
关键词[WOS]CYCLIC-ADP-RIBOSE ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HUMAN CD38 ; ENZYMATIC-SYNTHESIS ; STRUCTURAL BASIS ; ACTIVE-SITE ; NAADP ; HYDROLYSIS ; EXPRESSION ; CATALYSIS
英文摘要

The extracellular domain of human CD38 is a multifunctional enzyme involved in the metabolism of two Ca(2+) messengers: cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate. When NAD is used as substrate, CD38 predominantly hydrolyzes it to ADP-ribose, with a trace amount of cyclic ADP-ribose produced through cyclization of the substrate. However, mutation of a key residue at the active site, E146, inhibits the hydrolysis activity of CD38 but greatly increases its cyclization activity. To understand the role of the residue E146 in the catalytic process, we determined the crystal structure of the E146A mutant protein with a substrate analogue, arabinosyl-2′-fluoro-deoxy-nicotinamide adenine dinucleotide. The structure captured the enzymatic reaction intermediates in six different conformations in a crystallographic asymmetric unit. The structural results indicate a folding-back process for the adenine ring of the substrate and provide the first multiple snapshots of the process. Our approach of utilizing multiple molecules in the crystallographic asymmetric unit should be generally applicable for capturing the dynamic nature of enzymatic catalysis. (C) 2010 Elsevier Ltd. All rights reserved.

语种英语
WOS记录号WOS:000286962300013
项目编号GM061568 ; HKU 765909M ; HKU 769107M ; N_HKU 722/08
资助机构National Institutes of Health ; Research Grant Council of Hong Kong ; National Science Foundation of China
引用统计
被引频次:16[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/54052
专题北京大学药学院
北京大学药学院_药物化学系
北京大学第二临床医学院_妇科
作者单位1.Univ Hong Kong, Dept Physiol, Hong Kong, Hong Kong, Peoples R China
2.Univ Minnesota, Dept Physiol, Minneapolis, MN 55455 USA
3.Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
推荐引用方式
GB/T 7714
Zhang, HongMin,Graeff, Richard,Chen, Zhe,et al. Dynamic Conformations of the CD38-Mediated NAD Cyclization Captured in a Single Crystal[J]. JOURNAL OF MOLECULAR BIOLOGY,2011,405(4):1070-1078.
APA Zhang, HongMin.,Graeff, Richard.,Chen, Zhe.,Zhang, LiangRen.,Zhang, LiHe.,...&Hao, Quan.(2011).Dynamic Conformations of the CD38-Mediated NAD Cyclization Captured in a Single Crystal.JOURNAL OF MOLECULAR BIOLOGY,405(4),1070-1078.
MLA Zhang, HongMin,et al."Dynamic Conformations of the CD38-Mediated NAD Cyclization Captured in a Single Crystal".JOURNAL OF MOLECULAR BIOLOGY 405.4(2011):1070-1078.
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