Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution.
Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution.
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DOI：
10.1093/nar/gkl348
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发表时间：
2006
影响因子：
14.9
通讯作者：
Yang D
中科院分区：
文献类型：
--
作者：
Ambrus A;Chen D;Dai J;Bialis T;Jones RA;Yang D
人类端粒DNA由序列d（TTAGGG）的串联重复序列组成。端粒序列中DNA G-四链体的形成和稳定可抑制端粒酶活性，因此端粒DNA G-四链体被认为是肿瘤治疗的一个有吸引力的靶点。然而，在生理条件下形成的完整的人类端粒G-四链体结构的知识是基于结构的合理药物设计的先决条件。在这里，我们报告的折叠结构的人端粒序列在K+溶液中确定的NMR。我们的研究结果表明，一种新的，前所未有的分子内G-四链体折叠拓扑结构与混合型混合平行/反平行G-链。该端粒G-四链体结构包含三个G-四链体，它们具有混合的G-排列，它们通过双链反转侧环和两个侧环连续连接，每个侧环由三个核苷酸TTA组成。在K+溶液中形成的这种分子内混合型端粒G-四链体结构不同于在Na+溶液中和在K+存在下的结晶状态中的22 nt Tel 22上报道的那些，并且似乎是在K+存在下延伸的26 nt端粒序列Tel 26的主要构象，无论Na+的存在与否。此外，K+的加入容易地将Na+形式构象转化为K+形式的混合型G-四链体。我们的研究结果解释了所有报道的实验数据，在K+的存在下形成的人类端粒G-四链体，并提供重要的见解，了解多态性和相互转换的各种G-四链体结构内形成的人类端粒序列，以及序列和阳离子的影响。这种混合型G-四链体拓扑结构表明了一种直接的途径，用于二级结构的形成与有效的包装内扩展的人端粒DNA。混合型端粒G-四链体最有可能具有药理学相关性，并且这种G-四链体的独特折叠拓扑结构表明它可以被G-四链体相互作用的小分子药物特异性靶向。
Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG). The formation and stabilization of DNA G-quadruplexes in the human telomeric sequence have been shown to inhibit the activity of telomerase, thus the telomeric DNA G-quadruplex has been considered as an attractive target for cancer therapeutic intervention. However, knowledge of the intact human telomeric G-quadruplex structure(s) formed under physiological conditions is a prerequisite for structure-based rational drug design. Here we report the folding structure of the human telomeric sequence in K+ solution determined by NMR. Our results demonstrate a novel, unprecedented intramolecular G-quadruplex folding topology with hybrid-type mixed parallel/antiparallel G-strands. This telomeric G-quadruplex structure contains three G-tetrads with mixed G-arrangements, which are connected consecutively with a double-chain-reversal side loop and two lateral loops, each consisting of three nucleotides TTA. This intramolecular hybrid-type telomeric G-quadruplex structure formed in K+ solution is distinct from those reported on the 22 nt Tel22 in Na+ solution and in crystalline state in the presence of K+, and appears to be the predominant conformation for the extended 26 nt telomeric sequence Tel26 in the presence of K+, regardless of the presence or absence of Na+. Furthermore, the addition of K+ readily converts the Na+-form conformation to the K+-form hybrid-type G-quadruplex. Our results explain all the reported experimental data on the human telomeric G-quadruplexes formed in the presence of K+, and provide important insights for understanding the polymorphism and interconversion of various G-quadruplex structures formed within the human telomeric sequence, as well as the effects of sequence and cations. This hybrid-type G-quadruplex topology suggests a straightforward pathway for the secondary structure formation with effective packing within the extended human telomeric DNA. The hybrid-type telomeric G-quadruplex is most likely to be of pharmacological relevance, and the distinct folding topology of this G-quadruplex suggests that it can be specifically targeted by G-quadruplex interactive small molecule drugs.
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影响因子：
4.8
作者：
Dai, JX;Punchihewa, C;Yang, DZ
通讯作者：
Yang, DZ
DOI：
10.1016/0921-8734(91)90018-7
发表时间：
1991-03-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
HARLEY, CB
通讯作者：
HARLEY, CB
影响因子：
5.6
作者：
Kuryavyi, V;Kettani, A;Patel, DJ
通讯作者：
Patel, DJ
影响因子：
2
作者：
Kypr, J;Fialová, M;Vorlícková, M
通讯作者：
Vorlícková, M
影响因子：
4.8
作者：
Etzioni, S;Yafe, A;Fry, M
通讯作者：
Fry, M