Metal polypyridyl complex interactions with duplex and higher order DNAs

金属聚吡啶复合物与双链体和高阶 DNA 的相互作用

基本信息

  • 批准号:
    BB/K019279/1
  • 负责人:
  • 金额:
    $ 56.32万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2013
  • 资助国家:
    英国
  • 起止时间:
    2013 至 无数据
  • 项目状态:
    已结题

项目摘要

The double helix could be justifiably be called a scientific icon. Graphics showing the intertwined strands are used to market everything from hair shampoo to high-tech medical equipment. Yet we know remarkably little about exactly how molecules which are known to bind to DNA change its structure at the molecular level. Many do so by intercalation, that is, by adding an extra step to the DNA base stack, slipping in between the base pairs. This mode of binding lengthens the stack, and may cause DNA damage or mutation, but can also be of therapeutic benefit in cancer treatment.Intercalation can also form the basis of a method for detecting DNA. Some molecules, of which the best known is ethidium, intercalate and fluoresce, which makes them easy to visualise, DNA itself being colourless and not fluorescing in the visible region of the electromagnetic spectrum. The ruthenium 'light-switch' complexes we have recently studied show a much stronger fluorescence than ethidium, but, being metal complexes and chiral (showing handedness) they are a more complex system to understand. We have very recently shown that these complexes intercalate from the minor groove of DNA. We have also shown that the exact mode of binding depends on the DNA step, which is important in designing probes for specific DNA sequences. For example, if the left-handed molecule binds at a thymine-adenine step, it intercalates so deeply that it cannot form any other interactions. If, however, it binds at a guanine-guanine step, because the guanine base is larger, the ruthenium complex cannot intercalate so deeply into the minor groove. This means that a second 'arm' of the complex can interact with a second DNA duplex, causing kinking at that step, which is called semi-intercalation. This kinking behaviour probably occurs with other molecules, but this is the first time it has been directly visualised. We are not sure yet, whether these features can be put to direct use in cancer and related therapies, but a more immediate type of application is in the very sensitive detection of particular DNA sequences and shapes.In the present proposal, we aim, most importantly, to define for the first time, and making use of our currently world-leading position in the field, the exact shape-fitting which is necessary for the ruthenium complexes to 'click into place' at a particular step in the double helix. To understand this, we will look at ruthenium complexes having variable-shaped ligands, in combination with duplex-forming DNA sequences, together with some higher-order structures such as the quadruplexes (G-quartets) and the i-motif, found in single-stranded DNA at the ends of chromosomes in the telomeres. These specialised structures are associated with genetic switches, and it is estimated that there are perhaps 400,000 such regions in the human genome where such structures could form.We will carry out complementary solution studies, since a frequent question which arises is how we can know whether a molecule caught in the 'X-ray lens' of a crystal will show the same behaviour in the test tube (or indeed, in the living cell). Several solution measurements are sensitive to factors such as the orientation of a molecule in its binding pocket, the amount of access to water, whether or not another molecule is bound in an adjacent site, the DNA sequence, the pH, the salts present, and so forth. It is therefore important to relate the compact and immobile world of the crystal to that of the rapidly changing dilute solution used by spectroscopists, and it is a moot point, perhaps, which of the two may be closer to the tightly supercoiled and wound DNA of the chromosome.It is only by studying the crystal that we can know any molecular detail, which insight has then to be shared and related to these alternative viewpoints.
双螺旋结构可以毫无疑问地被称为科学图标。从洗发水到高科技医疗设备,各种各样的产品都有这种交织在一起的图案。然而,我们对已知与DNA结合的分子如何在分子水平上改变其结构知之甚少。许多是通过插入,也就是说,通过在DNA碱基堆上增加一个额外的步骤,在碱基对之间滑动。这种结合方式延长了堆叠,并且可能导致DNA损伤或突变,但也可以在癌症治疗中具有治疗益处。嵌入也可以形成检测DNA的方法的基础。一些分子,其中最著名的是乙锭,嵌入和荧光,这使得它们很容易可视化,DNA本身是无色的,在电磁光谱的可见区域不发荧光。我们最近研究的钌“光开关”络合物显示出比乙锭更强的荧光,但是,作为金属络合物和手性(显示手性),它们是一个更复杂的系统来理解。我们最近发现这些复合物从DNA的小沟插入。我们还表明,结合的确切模式取决于DNA步骤,这在设计针对特定DNA序列的探针时很重要。例如,如果左手分子在胸腺嘧啶-腺嘌呤步骤结合,它嵌入如此之深,以至于它不能形成任何其他相互作用。然而,如果它在鸟嘌呤-鸟嘌呤步骤结合,因为鸟嘌呤碱基较大,钌络合物不能如此深入地嵌入小沟。这意味着复合物的第二个“臂”可以与第二个DNA双链体相互作用,在该步骤引起扭结,这被称为半嵌入。这种扭结行为可能发生在其他分子中,但这是第一次直接可视化。我们还不确定这些特征是否可以直接用于癌症和相关治疗,但更直接的应用是对特定DNA序列和形状的非常灵敏的检测。在本提案中,我们的目标是,最重要的是,首次定义,并利用我们目前在该领域的世界领先地位,钌配合物在双螺旋中的特定步骤处“点击到位”所必需的精确形状配合。为了理解这一点,我们将研究具有可变形状配体的钌配合物,结合形成DNA的DNA序列,以及一些更高级的结构,如四链体(G-四联体)和i-基序,在端粒染色体末端的单链DNA中发现。这些特化结构与基因开关有关,据估计,人类基因组中可能有40万个这样的区域可以形成这样的结构。我们将进行补充解决方案研究,因为经常出现的一个问题是,我们如何知道被晶体的“X射线透镜”捕获的分子在试管中是否会表现出相同的行为(或在活细胞中)。几种溶液测量对诸如分子在其结合口袋中的取向、接近水的量、另一分子是否结合在相邻位点中、DNA序列、pH、存在的盐等因素敏感。因此,将晶体的紧密和固定的世界与光谱学家所用的快速变化的稀溶液的世界联系起来是很重要的。也许,这两者中哪一个更接近染色体的紧密超螺旋和缠绕的DNA是一个有争议的问题,只有通过研究晶体,我们才能知道任何分子的细节,然后这种见解必须与这些不同的观点分享和联系起来。

项目成果

期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The importance of loop length on the stability of i-motif structures
  • DOI:
    10.1039/c4cc07279k
  • 发表时间:
    2015-01-01
  • 期刊:
  • 影响因子:
    4.9
  • 作者:
    Gurung, Sarah P.;Schwarz, Christine;Brazier, John A.
  • 通讯作者:
    Brazier, John A.
Delta chirality ruthenium 'light-switch' complexes can bind in the minor groove of DNA with five different binding modes.
  • DOI:
    10.1093/nar/gkw753
  • 发表时间:
    2016-11-02
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Hall JP;Keane PM;Beer H;Buchner K;Winter G;Sorensen TL;Cardin DJ;Brazier JA;Cardin CJ
  • 通讯作者:
    Cardin CJ
The Structural Effect of Methyl Substitution on the Binding of Polypyridyl Ru-dppz Complexes to DNA
  • DOI:
    10.1021/om501208x
  • 发表时间:
    2015-06-08
  • 期刊:
  • 影响因子:
    2.8
  • 作者:
    Hall, James P.;Beer, Hanna;Cardin, Christine J.
  • 通讯作者:
    Cardin, Christine J.
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Christine Janet Cardin其他文献

Christine Janet Cardin的其他文献

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{{ truncateString('Christine Janet Cardin', 18)}}的其他基金

Ruthenium complex binding to DNA G-quadruplexes
与 DNA G 四链体结合的钌络合物
  • 批准号:
    BB/T008342/1
  • 财政年份:
    2020
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Research Grant
ETNA - Expansion of the Time domain in Nucleic Acid crystallography
ETNA - 核酸晶体学中时域的扩展
  • 批准号:
    BB/M004635/1
  • 财政年份:
    2014
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Research Grant

相似海外基金

Understanding and Controlling the Selectivity of Visible Light Photocatalysis in Metal Polypyridyl Artificial Metalloenzymes
了解和控制金属聚吡啶人工金属酶中可见光光催化的选择性
  • 批准号:
    2154726
  • 财政年份:
    2022
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Standard Grant
Metal polypyridyl complex interactions with duplex and higher order DNAs
金属聚吡啶复合物与双链体和高阶 DNA 的相互作用
  • 批准号:
    BB/K017128/1
  • 财政年份:
    2013
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Research Grant
Electron transfer in Cobalt complexes using rigid ferrocenyl decorated polypyridyl based ligands
使用刚性二茂铁基修饰的聚吡啶基配体在钴配合物中进行电子转移
  • 批准号:
    231408045
  • 财政年份:
    2013
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Research Grants
Photoinduced Electron Transfer Dynamics in a Tri-Nuclear Ru(H) Polypyridyl Assembly
三核 Ru(H) 聚吡啶基组装中的光致电子转移动力学
  • 批准号:
    336676-2006
  • 财政年份:
    2006
  • 资助金额:
    $ 56.32万
  • 项目类别:
    University Undergraduate Student Research Awards
Intercalation of ruthenium polypyridyl -based charge transfer polymers and telechelic olgomers in silicate sol-gels
硅酸盐溶胶-凝胶中钌聚吡啶基电荷转移聚合物和遥爪低聚物的插层
  • 批准号:
    121315-2004
  • 财政年份:
    2006
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Discovery Grants Program - Individual
Intercalation of ruthenium polypyridyl -based charge transfer polymers and telechelic olgomers in silicate sol-gels
硅酸盐溶胶-凝胶中钌聚吡啶基电荷转移聚合物和遥爪低聚物的插层
  • 批准号:
    121315-2004
  • 财政年份:
    2005
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Discovery Grants Program - Individual
DEUTERIUM ISOTOPE EFFECTS IN EXCITED STATE DECAY OF RUTHENIUM(LL) POLYPYRIDYL CO
氘同位素对钌(LL)聚吡啶钴激发态衰变的影响
  • 批准号:
    7170652
  • 财政年份:
    2005
  • 资助金额:
    $ 56.32万
  • 项目类别:
Intercalation of ruthenium polypyridyl -based charge transfer polymers and telechelic olgomers in silicate sol-gels
硅酸盐溶胶-凝胶中钌聚吡啶基电荷转移聚合物和遥爪低聚物的插层
  • 批准号:
    121315-2004
  • 财政年份:
    2004
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Discovery Grants Program - Individual
DEUTERIUM ISOTOPE EFFECTS IN EXCITED STATE DECAY OF RUTHENIUM(LL) POLYPYRIDYL CO
氘同位素对钌(LL)聚吡啶钴激发态衰变的影响
  • 批准号:
    6981607
  • 财政年份:
    2003
  • 资助金额:
    $ 56.32万
  • 项目类别:
Development of Novel Functionalized Organic Fluorescent Materials Having Polypyridyl Structure
具有聚吡啶结构的新型功能化有机荧光材料的研制
  • 批准号:
    10450339
  • 财政年份:
    1998
  • 资助金额:
    $ 56.32万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B).
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