Binding of topotecan to a nicked DNA oligomer in solution

Bocian W; Kawecki R; Bednarek E; Sitkowski J; Williamson MP; Hansen PE; Kozerski L

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Binding of topotecan to a nicked DNA oligomer in solution

机译：拓扑替康与溶液中带切口的DNA寡聚物的结合

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Topotecan (TPT) is in clinical use as an antitumor agent. It acts by binding to the covalent complex formed between nicked DNA and topoisomerase 1, and inserts itself into the single-strand nick, thereby inhibiting the religation of the nick and acting as a poison. A crystal structure analysis of the ternary complex has shown how the drug binds (B. L. Staker, K. Hjerrild, M. D. Feese, C. A. Behnke, A. B. Burgin, L. Stewart, Proc. Nad. Acad. Sci. US.A., 2002, 99, 15387-15392), but has left a number of unanswered questions. Herein, we use NMR spectroscopy and molecular modeling to show that the solution structure of a complex of TPT with nicked natural DNA is similar, but not identical to the crystal conformation, and that other geometries are of very low population. We also show that the lactone form of TPT binds approximately 40 times more strongly than the ring-opened carboxylate.

机译：拓扑替康（TPT）在临床上用作抗肿瘤药。它通过与带切口的DNA和拓扑异构酶1之间形成的共价复合物结合而起作用，并将其插入单链切口中，从而抑制了切口的重新结合并起毒物的作用。对三元复合物的晶体结构分析显示了该药物如何结合（BL Staker，K。Hjerrild，MD Feese，CA Behnke，AB Burgin，L.Stewart，Proc.Nad.Acad.Sci.US.A.，2002， 99，15387-15392），但留下了许多未解决的问题。在本文中，我们使用NMR光谱学和分子建模来显示TPT与带有切口的天然DNA的复合物的溶液结构相似，但与晶体构象不同，并且其他几何形状的种群非常少。我们还表明，内酯形式的TPT结合比开环羧酸酯结合约40倍。

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《Chemistry: A European journal》 |2008年第9期|共7页
作者
Bocian W; Kawecki R; Bednarek E; Sitkowski J; Williamson MP; Hansen PE; Kozerski L;
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正文语种 eng
中图分类化学;
关键词
alkaloids; antitumor agents; DNA binding; molecular dynamics; NMR spectroscopy; HUMAN TOPOISOMERASE-I; TERNARY CLEAVABLE COMPLEX; ANTITUMOR AGENTS; CAMPTOTHECIN DERIVATIVES; BINARY COMPLEX; RESP MODEL; NMR; MECHANISM; INHIBITION; COVALENT;

机译：生物碱;抗癌剂;DNA结合;分子动力学;NMR光谱;人拓扑异构酶-I;三级裂解复合物;抗原剂;喜树碱衍生物;二元复合物;RESP模型;NMR;机理;抑制剂;共价;

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专利

1. Binding of topotecan to a nicked DNA oligomer in solution [J] . Bocian W, Kawecki R, Bednarek E, Chemistry: A European journal . 2008,第9期

机译：拓扑替康与溶液中带切口的DNA寡聚物的结合
2. The DNA binding domain of human DNA ligase I interacts with both nicked DNA and the DNA sliding clamps, PCNA and hRad9-hRad1-hHus1. [J] . Song W, Pascal JM, Ellenberger T DNA repair . 2009,第8期

机译：人DNA连接酶I的DNA结合结构域与带切口的DNA和DNA滑动夹具PCNA和hRad9-hRad1-hHus1相互作用。
3. Interaction of Topotecan, DNA Topoisomerase I Inhibitor, with Double-Stranded Polydeoxyribonucleotides. 1. Topotecan Dimerization in Solution [J] . S.A.Streltsov, S.L.Grokhovskii, I.A.Kudelina, Molecular Biology . 2001,第3期

机译：DNA Topoisomerase I抑制剂Topotecan与双链聚脱氧核糖核苷酸的相互作用。 1.溶液中的拓扑替康二聚
4. New methods for DNA oligomer-binding and detection in the DNA microarray technology [C] . Andras Gyorffy International IEEE Conference on Polymers and Adhesives in Microelectronics and Photonics . 2002

机译：DNA微阵列技术中DNA低聚物结合和检测的新方法
5. Part I: Structural and functional insight into the type A CBFbeta-SMMHC protein and acute myeloid leukemia (AML). Part II: Solution structure of the HDGF PWWP domain and implications of its function as a DNA binding domain. [D] . Lukasik, Stephen Michael. 2006

机译：第一部分：对A型CBFbeta-SMMHC蛋白和急性髓细胞性白血病（AML）的结构和功能洞察。第二部分：HDGF PWWP域的溶液结构及其作为DNA结合域的功能的含义。
6. Nick sensing by vaccinia virus DNA ligase requires a 5 phosphate at the nick and occupancy of the adenylate binding site on the enzyme. [O] . J Sekiguchi, S Shuman 1997

机译：通过牛痘病毒DNA连接酶进行的尼克感测需要在切口处有一个5磷酸并占用该酶上腺苷酸结合位点。
7. The DNA binding domain of human DNA ligase I interacts with both nicked DNA and the DNA sliding clamps, PCNA and hRad9-hRad1-hHus1 [O] . Wei Song, John M. Pascal, Tom Ellenberger, 2009

机译：人DNA连接酶的DNA结合结构域I与卷曲DNA和DNA滑动夹，PCNA和HRAD9-HRAD1-HHUS1相互作用
8. NMR studies of DNA oligomers and their interactions with minor groove binding ligands [R] . Fagan, P. A. 1996

机译：DNa寡聚体的NmR研究及其与小沟结合配体的相互作用

Binding of topotecan to a nicked DNA oligomer in solution

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