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:
    6726795
  • 负责人:
  • 金额:
    $ 7.65万
  • 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 2006-04-30
  • 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(由申请人提供):2‘-5’寡聚腺苷酸合成酶(OAS)是一个酶家族,在哺乳动物先天免疫系统中发挥重要作用,赋予病毒感染的抵抗力。在干扰素刺激细胞后,产生潜伏性OAS,随后被双链RNA激活。活跃的OAS产生2‘-5’连接的低聚腺苷,它反过来二聚化并激活RNA酶L,一种降解细胞和病毒RNA的核糖核酸内酶。OAS的结构研究是有价值的,因为它们将为OAS 2'特异性核苷酸转移酶反应的机制以及酶的RNA激活提供见解。我们正在完成OAS蛋白的第一个晶体结构测定,即没有结合底物或激活RNA的潜伏酶的晶体结构测定。该结构揭示了与3'特异性聚合酶的结构相似性。对这种结构的分析为设计诱变实验以检验机制假设提供了基础,并为继续进行结构研究选择RNA结构提供了基础。

项目成果

期刊论文数量(0)
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VIVIEN YEE其他文献

VIVIEN YEE的其他文献

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{{ 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:
    $ 7.65万
  • 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:
    $ 7.65万
  • 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:
    $ 7.65万
  • 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:
    $ 7.65万
  • 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:
    $ 7.65万
  • 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:
    $ 7.65万
  • 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:
    6845525
  • 财政年份:
    2003
  • 资助金额:
    $ 7.65万
  • 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:
    $ 7.65万
  • 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:
    $ 7.65万
  • 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:
    $ 7.65万
  • 项目类别:

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