STRUCTURE & FUNCTION OF THE SV40 T-AG DNA BINDING DOMAIN
结构
基本信息
- 批准号:2872703
- 负责人:
- 金额:$ 25.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-02-01 至 2000-01-31
- 项目状态:已结题
- 来源:
- 关键词:DNA binding protein DNA replication DNA replication origin chemical binding chemical models computer simulation conformation gel mobility shift assay intermolecular interaction molecular site mutant nuclear magnetic resonance spectroscopy nucleic acid sequence protein structure function simian virus 40 site directed mutagenesis structural biology synthetic nucleotide tumor antigens virus genetics virus protein
项目摘要
Initiation of DNA replication is a complicated process that is understood
in only very broad terms. At present, the best eukaryotic model for
studies of initiation of DNA replication is the Simian Virus 40 (SV4O) in
vitro replication system. Initiation of SV4O replication requires a single
viral protein termed T-antigen (T-ag). Critical roles played by T.ag
during initiation of replication include site specific binding to the SV4O
origin, catalysis of subsequent unwinding events and recruitment of
additional proteins necessary for initiation of DNA synthesis. However,
our understanding of these events is limited owing to a lack of structural
information about T-ag or the T-ag DNA binding domain (T-ag-bd). The
following specific aims are proposed to address these issues.
I. To determine the structure of the DNA binding domain of SV4O T-antigen.
II. To characterize the biochemical properties of the T-ag-bd, and of
certain mutant forms of the T-ag-bd, and to examine the structures of
those mutant forms of the T-ag-bd with interesting properties.
III. To delineate the interaction of the T-ag-bd with DNA.
The work proposed in this application is significant from a basic science
standpoint because it will provide the first structure of a protein domain
that recognizes an origin of replication, whether from a prokaryotic or
eukaryotic source. Moreover, existing sequence data indicate the T-ag-bd
is not related to other known DNA binding proteins, suggesting the
structure may reveal a new protein structural motif. A knowledge of this
structure, or of the structure of this domain complexed to DNA, will
contribute significantly to advancing our understanding of replication by
revealing the protein/DNA contacts that enable specific recognition and
binding to an origin of replication.
The health related significance of the work proposed stems from the fact
that SV4O T-ag is very homologous to the T-ags encoded by the BK and JC
viruses. These viruses induce a number of diseases in humans, including
cancer. For example, JC virus induces progressive multifocal
leukoencephalopathy, a disease present in many AIDS patients.
DNA复制的启动是一个复杂的过程,
在非常广泛的意义上。目前,最好的真核生物模型
DNA复制起始的研究是猿猴病毒40(SV 4 O),
体外复制系统启动SV 4 O复制需要单个
称为T抗原(T-ag)的病毒蛋白。T.ag发挥的关键作用
包括与SV 4 O的位点特异性结合
起源、随后解旋事件的催化和
启动DNA合成所必需的额外蛋白质。然而,在这方面,
我们对这些事件的了解是有限的,因为缺乏结构性的
关于T-ag或T-ag DNA结合结构域(T-ag-bd)的信息。的
为解决这些问题,提出了以下具体目标。
I.确定SV 40 T抗原DNA结合域的结构。
二.为了表征T-ag-bd的生化特性,
某些突变形式的T-ag-bd,并检查结构的
那些具有有趣特性的T-ag-bd突变体。
三.描述T-ag-bd与DNA的相互作用。
本申请中提出的工作从一个基础科学的角度来说是有意义的
因为它将提供蛋白质结构域的第一个结构
识别复制起点,无论是来自原核生物还是
真核生物来源。此外,现有序列数据表明T-ag-bd
与其他已知的DNA结合蛋白无关,这表明
结构可能揭示了一个新的蛋白质结构基序。对此的了解
结构,或与DNA复合的结构域的结构,将
为我们进一步理解复制做出了重大贡献,
揭示蛋白质/DNA接触,使特异性识别,
与复制起点结合。
所提议的工作的健康相关意义源于以下事实:
SV 40 T-ag与BK和JC编码的T-ag非常同源
病毒这些病毒在人类中诱发多种疾病,包括
癌例如,JC病毒诱导进行性多灶性
白质脑病是许多艾滋病患者存在的一种疾病。
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)
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WILLIAM W BACHOVCHIN其他文献
WILLIAM W BACHOVCHIN的其他文献
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