Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif

Ina Buchholz; Beatrice Karg; Jonathan Dickerhoff; Adrian Sievers-Engler; Michael L-mmerhofer; Klaus Weisz

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Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif

机译：基于苯并噻唑基结合基序的G-Quadwlex结构的选择性靶向

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A benzothiazole derivative was identified as potent ligand for DNA G-quadruplex structures. Fluorescence titrations revealed selective binding to quadruplexes of different topologies including parallel, antiparallel, and (3+1) hybrid structures. The parallel c-MYC sequence was found to constitute the preferred target with dissociation constants in the micromolar range. Binding of the benzothiazole- based ligand to c-MYC was structurally and thermodynamically characterized in detail by employing a comprehensive set of spectroscopic and calorimetric techniques. Job plot analyses and mass spectral data indicate noncooperative ligand binding to form complexes with 1:1 and 2:1 stoichiometries. Whereas stacking interactions are suggested by optical methods, NMR chemical shift perturbations also indicate significant rearrangements of both 5'- and 3'-flanking sequences upon ligand binding. Additional isothermal calorimetry studies yield a thermodynamic profile of the ligand-quadruplex association and reveal enthalpic contributions to be the major driving force for binding. Structural and thermodynamic information obtained in the present work provides the basis for the rational development of benzothiazole derivatives as promising quadruplex binding agents.

机译：将苯并噻唑衍生物鉴定为DNA G-四逆转带结构的有效配体。荧光滴定显示出与不同拓扑的四翻转的选择性结合，包括平行，反平行和（3 + 1）杂化结构。发现并行C-MYC序列构成微摩尔范围内的解离常数的优选靶。基于苯并噻唑基配体与C-MYC的结合通过采用综合的光谱和量热技术来详细地进行结构和热力学地表征。作业曲线分析和质谱数据表示非杂种配体结合与1：1和2：1的化学物质形成复合物。虽然通过光学方法提出堆叠相互作用，但是NMR化学换档扰动还表明在配体结合时的5'-和3'侧序列的显着重排。额外的等温热量测压方法产生配体 - 四边形关联的热力学曲线，并揭示焓贡献，以成为结合的主要驱动力。本作中获得的结构和热力学信息为苯并噻唑衍生物作为承诺的Quadrupled粘合剂提供了基础。

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来源
《Chemistry: A European journal》 |2017年第24期|共10页
作者
Ina Buchholz; Beatrice Karg; Jonathan Dickerhoff; Adrian Sievers-Engler; Michael L-mmerhofer; Klaus Weisz;
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作者单位

Institute of Biochemistry Ernst-Moritz-Arndt University Greifswald Felix-Hausdorff-Strasse 4 17487 Greifswald (Germany);

Institute of Biochemistry Ernst-Moritz-Arndt University Greifswald Felix-Hausdorff-Strasse 4 17487 Greifswald (Germany);

Institute of Biochemistry Ernst-Moritz-Arndt University Greifswald Felix-Hausdorff-Strasse 4 17487 Greifswald (Germany);

Institute of Pharmaceutical Sciences Eberhard Karls University Tebingen Auf der Morgenstelle 8 72076 Tebingen (Germany);

Institute of Pharmaceutical Sciences Eberhard Karls University Tebingen Auf der Morgenstelle 8 72076 Tebingen (Germany);

Institute of Biochemistry Ernst-Moritz-Arndt University Greifswald Felix-Hausdorff-Strasse 4 17487 Greifswald (Germany);

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原文格式 PDF
正文语种 eng
中图分类应用化学;
关键词
G-quadruplexes; ligand effects; molecular recognition; NMR spectroscopy; noncovalent interactions;

机译：G-quadrupleces;配体效果;分子识别;NMR光谱;非价相互作用;

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专利

1. Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif [J] . Ina Buchholz, Beatrice Karg, Jonathan Dickerhoff, Chemistry: A European journal . 2017,第24期

机译：基于苯并噻唑基结合基序的G-Quadwlex结构的选择性靶向
2. Loop Lengths of G-Quadruplex Structures Affect the G-Quadruplex DNA Binding Selectivity of the RGG Motif in Ewing’s Sarcoma [J] . Kentaro Takahama Chieri Sugimoto Shigeki Arai Riki Kurokawa and Takanori Oyoshi Biochemistry . 2011,第23期

机译：G四联体结构的环长度影响尤因肉瘤中RGG基序的G四联体DNA结合选择性。
3. Loop Lengths of G-Quadruplex Structures Affect the G-Quadruplex DNA Binding Selectivity of the RGG Motif in Ewing's Sarcoma [J] . Takahama K, Sugimoto C, Arai S, Biochemistry . 2011,第23期

机译：G-QuadrupleS结构的循环长度影响ewing的肉瘤中RGG主题的G-Quadrepled DNA结合选择性
4. Title: Verification of specific G-quadruplex structure by using a novel cyanine dye supramolecular assembly: Ⅱ. The binding characterization with specific intramolecular G-quadruplex and the recognizing mechanism [C] . Qianfan Yang, Guangzhi Xu, Junfeng Xiang, ICMSI;International conference of molecular simulations and applied informatics technologies . 2010

机译：标题：通过使用新型花青染料超分子组装验证特定的G-四链体结构：Ⅱ。特定分子内G-四链体的结合表征及识别机理
5. Interactions of DNA binding proteins with G-Quadruplex structures at the single molecule level [D] . Ray, Sujay 2014

机译：DNA结合蛋白与G-四链体结构在单分子水平上的相互作用
6. The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression [O] . Daekyu Sun, Laurence H. Hurley -1

机译：负superhelicity的诱导在c-myc的启动子G-四链和i-基序结构的形成的重要性：用于药物靶向的影响和基因表达的控制
7. Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs [O] . Amit Ketkar, Lane Smith, Callie Johnson, 2021

机译：人Rev1依赖于插入-2以促进稳定的G-QuadRuple Polifs的选择性结合和准确复制

Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif

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