The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP
Zhu, CF; Wei W(魏伟); Wei, W; Peng, X; Dong, YH; Gong, Y; Yu, XF; Dong YH(董宇辉); Gong Y(龚勇)
刊名ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
2015
卷号71期号:3页码:516-524
关键词SAMHD1 substrate-controlled allosteric regulation
学科分类Biochemistry & Molecular Biology; Biophysics; Crystallography
DOI10.1107/S1399004714027527
通讯作者龚勇
文章类型Article
英文摘要SAMHD1 is the only known eukaryotic deoxynucleoside triphosphate triphosphohydrolase (dNTPase) and is a major regulator of intracellular dNTP pools. It has been reported to be a potent inhibitor of retroviruses such as HIV-1 and endogenous retrotransposons. Previous crystal structures have revealed that SAMHD1 is activated by dGTP-dependent tetramer formation. However, recent data have indicated that the primary activator of SAMHD1 is GTP, not dGTP. Therefore, how its dNTPase activity is regulated needs to be further clarified. Here, five crystal structures of the catalytic core of SAMHD1 in complex with different combinations of GTP and dNTPs are reported, including a GTP-bound dimer and four GTP/dNTP-bound tetramers. The data show that human SAMHD1 contains two unique activator-binding sites in the allosteric pocket. The primary activator GTP binds to one site and the substrate dNTP (dATP, dCTP, dUTP or dTTP) occupies the other. Consequently, both GTP and dNTP are required for tetramer activation of the enzyme. In the absence of substrate binding, SAMHD1 adopts an inactive dimer conformation even when complexed with GTP. Furthermore, SAMHD1 activation is regulated by the concentration of dNTP. Thus, the level of dNTP pools is elegantly regulated by the self-sensing ability of SAMHD1 through a novel activation mechanism.
类目[WOS]Biochemical Research Methods ; Biochemistry & Molecular Biology ; Biophysics ; Crystallography
收录类别SCI
WOS记录号WOS:000351155400010
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被引频次:12[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.ihep.ac.cn/handle/311005/228245
专题中国科学院高能物理研究所_多学科研究中心_期刊论文
中国科学院高能物理研究所_多学科研究中心
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Zhu, CF,Wei W,Wei, W,et al. The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP[J]. ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY,2015,71(3):516-524.
APA Zhu, CF.,魏伟.,Wei, W.,Peng, X.,Dong, YH.,...&龚勇.(2015).The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP.ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY,71(3),516-524.
MLA Zhu, CF,et al."The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP".ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY 71.3(2015):516-524.
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