Thermodynamic Origins of Sequence-Recognition in Ligand-DNA Interactions

配体-DNA 相互作用中序列识别的热力学起源

基本信息

  • 批准号:
    0334785
  • 负责人:
  • 金额:
    $ 25.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-05-01 至 2006-03-31
  • 项目状态:
    已结题

项目摘要

Graves, David E.MCB-0092177The long-term objective of this research is to gain biophysical insight into the key aspects of sequence selective interactions of small molecules with nucleic acids. The model system that has been studied thus far involves the sequence-specific DNA binding agent, actinomycin D. This compounds shows a marked preference for DNA binding at the d(GpC) step through intercalation of the phenoxazone chromophore between the adjacent G and C base pairs. Concomitant with this intercalative binding is the interactions of the two cyclic pentapeptide sidechains with the floor of the DNA minor groove. This laboratory has recently demonstrated the bases that flank this intercalation site play a major role in directing the thermodynamic mechanism for complex formation. If the 5'-flanking sequence is T (-TGCA-), the change in binding enthalpy has been measured to be -2.5 kcal/mol. In contrast, when the 5'-flanking base is C (-CGCA-), the change in binding enthalpy is found to be -5.8 kcal/mol, nearly 3 kcal/mol more favorable than the other flanking sequences. 5 Historically, the binding of actinomycin D to DNA has been reported to be enthalpy driven as signified by large positive (favorable) binding enthalpies and binding enthalpies of near zero or -1 kcal/mol. These recent results from this laboratory indicate that the thermodynamic binding properties of actinomycin D to oligonucleotides with specifically designed single binding sites are quite varied, depending on the sequence of bases flanking the actinomycin D binding site. Based on the variances observed in the enthalpy and entropy components associated with complex formation, linkages between thermodynamic binding mechanism(s) and structural features of the actinomycin D-DNA complexeswil be explored. Specifically the structures of the actinomycin D complexes formed with the -TGCA- duplex and the -CGCA- duplex will be examined by high-resolution NMR methods to discern differences in the structural features of the complex that may explain the enhanced enthalpy contribution toward actinomycin D binding to the CGCA- duplex.The use of non-self complimentary deoxyoligonucleotides was serendipitous toward the finding ofsequence selective interactions of actinomycin D to single-strand DNA. The influence of DNA base sequence on the energetics and structural properties of actinomycin D-single strand DNA interactions is being examined. These observations could be of considerable benefit in gaining insight into how proteins bind single-strand DNA in a sequence-selective manner and expanded to biological roles of single-strand DNA interactions. The in vivo interactions of actinomycin D to double stranded DNA are characterized by high affinity and slow dissociation and have been suggested to carry out their biological function of specifically inhibiting transcription through blocking the progression of the RNA polymerase along the DNA template. With the recent findings of a high affinity of actinomycin D for single-stranded DNA, additional caveats may be added to this proposed mechanism, including the possible binding of the drug to single-strand DNA within the open complex, and/or to inhibiting reannealing of the single-strand DNA.
Graves, David E.MCB-0092177 这项研究的长期目标是获得对小分子与核酸的序列选择性相互作用的关键方面的生物物理学见解。迄今为止已研究的模型系统涉及序列特异性 DNA 结合剂放线菌素 D。该化合物通过在相邻 G 和 C 碱基对之间插入吩恶宗发色团,在 d(GpC) 步骤显示出对 DNA 结合的明显偏好。 与这种插入结合相伴的是两条环状五肽侧链与 DNA 小沟底部的相互作用。 该实验室最近证明了该嵌入位点两侧的碱基在指导复合物形成的热力学机制中发挥着重要作用。 如果 5'-侧翼序列是 T (-TGCA-),则结合焓的变化经测量为 -2.5 kcal/mol。相反,当5'-侧翼碱基为C(-CGCA-)时,发现结合焓的变化为-5.8 kcal/mol,比其他侧翼序列有利近3 kcal/mol。 5 历史上,据报道放线菌素 D 与 DNA 的结合是由焓驱动的,表现为大的正(有利)结合焓和接近零或 -1 kcal/mol 的结合焓。该实验室的这些最新结果表明,放线菌素 D 与具有专门设计的单一结合位点的寡核苷酸的热力学结合特性差异很大,具体取决于放线菌素 D 结合位点两侧的碱基序列。基于在与复合物形成相关的焓和熵分量中观察到的变化,将探索放线菌素 D-DNA 复合物的热力学结合机制和结构特征之间的联系。 具体而言,将通过高分辨率NMR方法检查与-TGCA-双链体和-CGCA-双链体形成的放线菌素D复合物的结构,以辨别复合物结构特征的差异,这可以解释放线菌素D与CGCA-双链体结合的焓贡献增加。非自互补脱氧寡核苷酸的使用是 偶然发现放线菌素 D 与单链 DNA 的序列选择性相互作用。 DNA 碱基序列对放线菌素 D-单链 DNA 相互作用的能量学和结构特性的影响正在研究中。这些观察结果对于深入了解蛋白质如何以序列选择性方式结合单链 DNA 以及扩展到单链 DNA 相互作用的生物学作用具有相当大的好处。放线菌素 D 与双链 DNA 的体内相互作用具有高亲和力和缓慢解离的特点,并被认为通过阻断 RNA 聚合酶沿 DNA 模板的进展来实现特异性抑制转录的生物学功能。最近发现放线菌素 D 对单链 DNA 具有高亲和力,因此可能会对这一提议的机制添加额外的警告,包括药物可能与开放复合物内的单链 DNA 结合,和/或抑制单链 DNA 的重新退火。

项目成果

期刊论文数量(0)
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David Graves其他文献

The institutional theory of art: A survey
  • DOI:
    10.1007/bf02380024
  • 发表时间:
    1997-04-01
  • 期刊:
  • 影响因子:
    0.500
  • 作者:
    David Graves
  • 通讯作者:
    David Graves
Distribution of Off-Label Information By Pharmaceutical Manufacturers?

David Graves的其他文献

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{{ truncateString('David Graves', 18)}}的其他基金

INFEWS N/P/H2O: Fundamentals of N2/O2 plasma and heterogeneous catalysis
INFEWS N/P/H2O:N2/O2 等离子体和多相催化的基础知识
  • 批准号:
    1606062
  • 财政年份:
    2016
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
Collaborative Research: Atmospheric Pressure Plasma-Biomaterial Interactions - Bridging Understanding Of APP Sources To Rational Modification Of Biomolecules
合作研究:大气压等离子体-生物材料相互作用 - 将 APP 来源的理解与生物分子的合理修饰联系起来
  • 批准号:
    1415022
  • 财政年份:
    2014
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Continuing Grant
Thermodynamic Origins of Sequence-Recognition in Ligand-DNA Interactions
配体-DNA 相互作用中序列识别的热力学起源
  • 批准号:
    0092177
  • 财政年份:
    2001
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Continuing Grant
Plasma Processing Science Gordon Research Conference
等离子体处理科学戈登研究会议
  • 批准号:
    0084414
  • 财政年份:
    2000
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
Gordon Research Conference on Plasma Processing Science; Tilton, New Hampshire; August 9-14, 1998
戈登等离子体处理科学研究会议;
  • 批准号:
    9813339
  • 财政年份:
    1998
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
Thermodynamic Origins of Sequence-Recognition in Ligand-DNA Interactions
配体-DNA 相互作用中序列识别的热力学起源
  • 批准号:
    9728720
  • 财政年份:
    1998
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
1995 Gaseous Electronics Conference Student Support Berkeley, California
1995 年气体电子会议学生支持加州伯克利
  • 批准号:
    9527684
  • 财政年份:
    1995
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
Acquisition of a 400 MHz NMR Spectrometer
购买 400 MHz NMR 波谱仪
  • 批准号:
    9413721
  • 财政年份:
    1994
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
Development of a Modular Laboratory Course in Biotechnology and Biochemical Engineering
生物技术和生化工程模块化实验室课程的开发
  • 批准号:
    9315283
  • 财政年份:
    1993
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant
Reversed Phase Chromatography in a Magnetically Stabilized Fluidized Bed
磁稳定流化床反相色谱
  • 批准号:
    8820150
  • 财政年份:
    1989
  • 资助金额:
    $ 25.43万
  • 项目类别:
    Standard Grant

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