Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway.
Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway.
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DOI：
10.1093/nar/gky1092
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发表时间：
2018-12-14
影响因子：
14.9
通讯作者：
Paciaroni A
中科院分区：
文献类型：
--
作者：
Bianchi F;Comez L;Biehl R;D'Amico F;Gessini A;Longo M;Masciovecchio C;Petrillo C;Radulescu A;Rossi B;Sacchetti F;Sebastiani F;Violini N;Paciaroni A
结合圆二色光谱、紫外共振拉曼光谱和小角散射技术的多技术方法已被用来阐明人类端粒 G-四链体 d[A(GGGTTA)3GGG] (Tel22) 的结构特征在热展开时如何变化。该系统以游离形式和与放线菌素 D (ActD) 结合时进行了研究，放线菌素 D 是一种具有显着构象灵活性的抗癌配体。我们发现在室温下 Tel22 与 ActD 的结合涉及末端 G-四分体上的末端堆积。提供了药物驱动的大部分 G 四链体二聚化的结构证据。当温度升高时，游离和结合的 Tel22 都会通过多态过程发生熔化。我们发现，在 Tel22 的中间状态下，构象平衡向 (3+1) 混合型移动，同时在复合物中促进了平行结构。游离 Tel22 的未折叠状态与自回避随机螺旋构象一致，而观察到复合物的高温状态呈现出相当紧凑的形式。这种前所未有的高温排列是由 Tel22 和 ActD 之间的持续相互作用引起的，即使存在较大的热结构波动，也能稳定紧凑的构象。
A multi-technique approach, combining circular dichroism spectroscopy, ultraviolet resonance Raman spectroscopy and small angle scattering techniques, has been deployed to elucidate how the structural features of the human telomeric G-quadruplex d[A(GGGTTA)3GGG] (Tel22) change upon thermal unfolding. The system is studied both in the free form and when it is bound to Actinomycin D (ActD), an anticancer ligand with remarkable conformational flexibility. We find that at room temperature binding of Tel22 with ActD involves end-stacking upon the terminal G-tetrad. Structural evidence for drug-driven dimerization of a significant fraction of the G-quadruplexes is provided. When the temperature is raised, both free and bound Tel22 undergo melting through a multi-state process. We show that in the intermediate states of Tel22 the conformational equilibrium is shifted toward the (3+1) hybrid-type, while a parallel structure is promoted in the complex. The unfolded state of the free Tel22 is consistent with a self-avoiding random-coil conformation, whereas the high-temperature state of the complex is observed to assume a quite compact form. Such an unprecedented high-temperature arrangement is caused by the persistent interaction between Tel22 and ActD, which stabilizes compact conformations even in the presence of large thermal structural fluctuations.
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影响因子：
4.6
作者：
Bergues-Pupo AE;Gutiérrez I;Arias-Gonzalez JR;Falo F;Fiasconaro A
通讯作者：
Fiasconaro A
影响因子：
15
作者：
FODOR, SPA;RAVA, RP;SPIRO, TG
通讯作者：
SPIRO, TG
DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.9
作者：
Ambrus A;Chen D;Dai J;Bialis T;Jones RA;Yang D
通讯作者：
Yang D
影响因子：
14.9
作者：
Kypr J;Kejnovská I;Renciuk D;Vorlícková M
通讯作者：
Vorlícková M