Structure-function studies of an antiviral enzyme

抗病毒酶的结构功能研究

基本信息

  • 批准号:
    6845525
  • 负责人:
  • 金额:
    $ 6.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-05-01 至 2005-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The 2'-5' oligoadenylate synthetases (OAS) are a family of enzymes which play an important role in the mammalian innate immune system by conferring resistance to viral infections. Upon interferon stimulation of cells, latent OAS is produced and subsequently activated by double-stranded RNA. Active OAS produces 2'-5' linked oligoadenosines which in turn dimerize and activate RNase L, an endoribonuclease that degrades cellular and viral RNA. Structural studies of OAS are valuable since they will provide insight into the mechanisms for the OAS 2'-specific nucleotidyl transferase reaction, and for the RNA activation of the enzyme. We are in the process of completing the first crystal structure determination of an OAS protein, that of a latent enzyme without bound substrate or activating RNA. This structure reveals a structural similarity with 3'-specific polymerases. Analysis of this structure provides a basis for designing mutagenesis experiments to test mechanistic hypotheses, and for selecting RNA constructs for continuing structural studies. From the comparison between the OAS active site and those in 3'-specific polymerases, we hypothesize that the mechanisms for the 2' and 3' nucleotidyl transferase reactions are similar, and that the 2' specificity may arise from a differing position of the substrate. Specific Aim 1 is to investigate the components of the OAS catalytic machinery which are responsible for the unique 2' specificity of its nucleotidyl transferase reaction. This will be done by observing the functional consequences of designed mutants in which proposed active site amino acid residues have been substituted, and by pursuing crystal structures of OAS bound to ATP substrate, 2-5A substrate/product, or analogs. These efforts constitute a small, self-contained project which can be carried out with modest resources. From the analysis of our apo OAS crystal structure, we hypothesize that OAS activation requires a conformational change of the protein which likely occurs upon RNA binding. Specific Aim 2 is to investigate the mechanism of OAS recognition of viral RNA, and of the subsequent activation of the OAS enzyme by double-stranded RNA. Crystals of complexes of OAS bound to activating double-stranded RNA, or to non-activating single-stranded RNA, will be pursued. These crystallization experiments for OAS-RNA complexes are feasibility studies for the development of the OAS project, which is a new direction for the Principal Investigator's laboratory.
描述(申请人提供):2‘-5’寡腺苷合成酶(OAS)是一个酶家族,通过赋予对病毒感染的抵抗力,在哺乳动物的先天免疫系统中发挥重要作用。当干扰素刺激细胞时,潜伏的OAS被产生,随后被双链RNA激活。活跃的OAS产生2‘-5’连接的寡腺苷二聚体并激活核糖核酸酶L,核糖核酸酶是一种降解细胞和病毒核糖核酸的内切核酸酶。OAS的结构研究是有价值的,因为它们将为OAS 2‘特异的核苷酸转移酶反应和该酶的RNA激活提供深入的机制。我们正在完成OAS蛋白质的第一次晶体结构测定,这是一种没有结合底物或激活RNA的潜伏酶。这种结构显示出与3‘-特异性聚合酶的结构相似。对这种结构的分析为设计突变实验以检验机制假说和选择RNA结构进行继续结构研究提供了基础。 通过对OAS活性部位和3‘-特异性聚合酶活性部位的比较,我们推测2’和3‘核苷酸转移酶反应的机制是相似的,2’-特异性可能来自底物的不同位置。具体目的1是研究OAS催化机械的部件,这些部件负责其核苷酸转移酶反应独特的2‘特异性。这将通过观察设计的突变体的功能后果,其中建议的活性部位氨基酸残基已被取代,并通过追求与ATP底物、2-5A底物/产物或类似物结合的OAS的晶体结构来实现。这些努力构成了一个小型、自给自足的项目,可以用不多的资源进行。从对apo OAS晶体结构的分析中,我们假设OAS的激活需要蛋白质的构象变化,这可能发生在RNA结合时。具体目的2是研究OAS识别病毒RNA的机制,以及双链RNA随后激活OAS酶的机制。将寻求与激活的双链RNA或非激活的单链RNA结合的OAS络合物的晶体。这些对OAS-RNA复合体的结晶实验是OAS项目发展的可行性研究,这是首席研究员实验室的一个新方向。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

VIVIEN YEE其他文献

VIVIEN YEE的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('VIVIEN YEE', 18)}}的其他基金

CRYSTAL STRUCTURE OF A TRANSCARBOXYLASE (TC) MULTIENZYME COMPLEX
转羧酶 (TC) 多酶复合物的晶体结构
  • 批准号:
    8169332
  • 财政年份:
    2010
  • 资助金额:
    $ 6.33万
  • 项目类别:
Structural biology of biotin-dependent carboxylases
生物素依赖性羧化酶的结构生物学
  • 批准号:
    8008942
  • 财政年份:
    2010
  • 资助金额:
    $ 6.33万
  • 项目类别:
TRANSCARBOXYLASE, A 12MDA MULTIENZYME COMPLEX
转羧酶,一种 12MDA 多酶复合物
  • 批准号:
    7726278
  • 财政年份:
    2008
  • 资助金额:
    $ 6.33万
  • 项目类别:
Structural biology of biotin-dependent carboxylases
生物素依赖性羧化酶的结构生物学
  • 批准号:
    7546538
  • 财政年份:
    2008
  • 资助金额:
    $ 6.33万
  • 项目类别:
Structural biology of biotin-dependent carboxylases
生物素依赖性羧化酶的结构生物学
  • 批准号:
    8009397
  • 财政年份:
    2008
  • 资助金额:
    $ 6.33万
  • 项目类别:
TRANSCARBOXYLASE, A 12MDA MULTIENZYME COMPLEX
转羧酶,一种 12MDA 多酶复合物
  • 批准号:
    7602345
  • 财政年份:
    2007
  • 资助金额:
    $ 6.33万
  • 项目类别:
Structure-function studies of an antiviral enzyme
抗病毒酶的结构功能研究
  • 批准号:
    6595854
  • 财政年份:
    2003
  • 资助金额:
    $ 6.33万
  • 项目类别:
Structure-function studies of an antiviral enzyme
抗病毒酶的结构功能研究
  • 批准号:
    6726795
  • 财政年份:
    2003
  • 资助金额:
    $ 6.33万
  • 项目类别:
CRYSTALLOGRAPHIC STUDY OF HUMAN RECOMBINANT FACTOR XIII
人类重组因子 XIII 的晶体学研究
  • 批准号:
    6658548
  • 财政年份:
    2002
  • 资助金额:
    $ 6.33万
  • 项目类别:
CRYSTALLOGRAPHIC STUDY OF HUMAN RECOMBINANT FACTOR XIII
人类重组因子 XIII 的晶体学研究
  • 批准号:
    6586581
  • 财政年份:
    2002
  • 资助金额:
    $ 6.33万
  • 项目类别:

相似海外基金

Late-Stage Functionalisation of Cyclic Guanosine Monophosphate - Adenosine Monophosphate
环单磷酸鸟苷-单磷酸腺苷的后期功能化
  • 批准号:
    2751533
  • 财政年份:
    2022
  • 资助金额:
    $ 6.33万
  • 项目类别:
    Studentship
The Role of Chronic Pharmacological Adenosine Monophosphate-Activated Protein Kinase Activation at the Neuromuscular Junction
慢性药理学单磷酸腺苷激活蛋白激酶激活在神经肌肉接头处的作用
  • 批准号:
    575833-2022
  • 财政年份:
    2022
  • 资助金额:
    $ 6.33万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Master's
Targeting adenosine monophosphate activated protein kinase (AMPK) to reduce cocaine relapse
靶向单磷酸腺苷激活蛋白激酶 (AMPK) 减少可卡因复吸
  • 批准号:
    10593045
  • 财政年份:
    2022
  • 资助金额:
    $ 6.33万
  • 项目类别:
Targeting adenosine monophosphate activated protein kinase (AMPK) to reduce cocaine relapse
靶向单磷酸腺苷激活蛋白激酶 (AMPK) 减少可卡因复吸
  • 批准号:
    10303255
  • 财政年份:
    2022
  • 资助金额:
    $ 6.33万
  • 项目类别:
The regulation of electrical coupling between neuroendocrine cells by cyclic adenosine monophosphate and protein kinase A
环磷酸腺苷与蛋白激酶A对神经内分泌细胞电耦合的调节
  • 批准号:
    565217-2021
  • 财政年份:
    2021
  • 资助金额:
    $ 6.33万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Master's
Dissecting the Molecular Mechanisms of the Histone Acetyltransferase/Cyclic Adenosine Monophosphate Binding Protein Interactome Using Protein-Observed Fluorine NMR
使用蛋白质观察的氟 NMR 剖析组蛋白乙酰转移酶/环单磷酸腺苷结合蛋白相互作用组的分子机制
  • 批准号:
    1904071
  • 财政年份:
    2019
  • 资助金额:
    $ 6.33万
  • 项目类别:
    Standard Grant
Osmotic stress regulation and the role of cyclic di-adenosine monophosphate (c-di-AMP) in Staphylococcus aureus
金黄色葡萄球菌的渗透应激调节和环二腺苷单磷酸 (c-di-AMP) 的作用
  • 批准号:
    318765828
  • 财政年份:
    2016
  • 资助金额:
    $ 6.33万
  • 项目类别:
    Research Fellowships
Novel mechanisms controlling signaling by adenosine monophosphate-activated protein kinase, central regulator of energy homeostasis
通过单磷酸腺苷激活蛋白激酶控制信号传导的新机制,能量稳态的中央调节器
  • 批准号:
    FT130100988
  • 财政年份:
    2014
  • 资助金额:
    $ 6.33万
  • 项目类别:
    ARC Future Fellowships
The roles of cyclic adenosine monophosphate (cAMP) in suppressive functions of regulatory T cells
环磷酸腺苷 (cAMP) 在调节性 T 细胞抑制功能中的作用
  • 批准号:
    25893115
  • 财政年份:
    2013
  • 资助金额:
    $ 6.33万
  • 项目类别:
    Grant-in-Aid for Research Activity Start-up
Molecular mechanisms of cyclic Adenosine Monophosphate (AMP) induced apoptosis
环磷酸腺苷(AMP)诱导细胞凋亡的分子机制
  • 批准号:
    DP110100417
  • 财政年份:
    2011
  • 资助金额:
    $ 6.33万
  • 项目类别:
    Discovery Projects
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了