Topology conservation and loop flexibility in quadruplex-drug recognition: Crystal structures of inter- and intramolecular telomeric DNA quadruplex-drug complexes
Topology conservation and loop flexibility in quadruplex-drug recognition: Crystal structures of inter- and intramolecular telomeric DNA quadruplex-drug complexes
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DOI：
10.1016/j.jmb.2008.06.022
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发表时间：
2008-09-19
影响因子：
5.6
通讯作者：
Neidle, Stephen
中科院分区：
文献类型：
--
作者：
Parkinson, Gary N.;Cuenca, Francisco;Neidle, Stephen
生物学相关拓扑结构的知识对于设计靶向四链体核酸的药物是至关重要的。我们在这里报告的晶体结构的G-四链体选择性配体与两个人类端粒DNA四链体。分子内四链体序列d[TAGGG（TTAGGG）（3）]和双分子四链体序列d（TAGGGT-TAGGGT）与四取代萘二酰亚胺四链体结合配体共结晶。的结构进行了解决和细化到2.10-和2.20埃的分辨率，分别揭示了四链体拓扑结构在两种结构是不变的，通过添加配体，保留了平行链的安排与外部双链反转螺旋桨环。平行拓扑结构导致可接近的外部5'和3'平面G-四联体表面用于配体堆叠。这也使得在几个TTA螺旋桨环中发生显著的配体诱导的构象变化，使得环本身能够通过在外部TTA连接环核苷酸上堆叠来容纳结合的药物分子而不影响平行四链体拓扑结构。配体结合到外部TTA环核苷酸中并堆叠到G-四联体表面上。这些晶体结构为萘二酰亚胺系列的进一步配体发展提供了框架，以提高选择性和亲和力。(c)2008爱思唯尔有限公司保留所有权利。
Knowledge of the biologically relevant topology is critical for the design of drugs targeting quadruplex nucleic acids. We report here crystal structures of a G-quadruplex-selective ligand complexed with two human telomeric DNA quadruplexes. The intramolecular quadruplex sequence d[TAGGG (TTAGGG)(3)] and the bimolecular quadruplex sequence d(TAGGGT-TAGGGT) were co-crystallized with a tetra-substituted naphthalene diimide quadruplex-binding ligand. The structures were solved and refined to 2.10- and 2.20-angstrom resolution, respectively, revealing that the quadruplex topology in both structures is unchanged by the addition of the ligands, retaining a parallel-stranded arrangement with external double-chain-reversal propeller loops. The parallel topology results in accessible external 5' and 3' planar G-tetrad surfaces for ligand stacking. This also enables significant ligand-induced conformational changes in several TTA propeller loops to take place such that the loops themselves are able to accommodate bound drug molecules without affecting the parallel quadruplex topology, by stacking on the external TTA connecting loop nucleotides. Ligands are bound into the external TTA loop nucleotides and stack onto G-tetrad surfaces. These crystal structures provide a framework for further ligand development of the naphthalene diimide series to enhance selectivity and affinity. (c) 2008 Elsevier Ltd. All rights reserved.