Structural basis for binding of porphyrin to human telomeres
Structural basis for binding of porphyrin to human telomeres
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DOI：
10.1021/bi062244n
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发表时间：
2007-03-06
期刊：
影响因子：
2.9
通讯作者：
Neidle, Stephen
中科院分区：
文献类型：
--
作者：
Parkinson, Gary N.;Ghosh, Ragini;Neidle, Stephen
端粒完整性的维持是人类癌症的标志，并且端粒DNA的单链3'末端是小分子抗癌疗法的靶标。本文报道了一种双分子人端粒四链体的晶体结构，其序列为d（TAGGGTTAGGG），与四链体结合配体5，10，15，20-四（N-甲基-4-吡啶基）卟啉（TMPyP 4）形成复合物，其分辨率为2.09 A。DNA四链体拓扑结构是平行链的外部双链反转螺旋桨环，与以前的结构确定一致。卟啉分子通过堆叠到TTA核苷酸上结合，作为外部环结构的一部分或在堆叠的四链体的5'区域。这涉及堆叠在由不参与G-四联体形成的那些核苷酸形成的氢键碱基对上，因此不存在与G-四联体的直接配体相互作用。这与TMPyP 4对四链体DNA相比于双链体DNA的相对非选择性雅阁。与无配体结构相比，卟啉结合是通过环的重塑实现的。四链体结合配体的设计的影响进行了讨论，连同一个模型形成的后期桥梁，这是观察到细胞治疗与TMPyP 4。
Maintenance of telomere integrity is a hallmark of human cancer, and the single-stranded 3' ends of telomeric DNA are targets for small-molecule anticancer therapies. We report here the crystal structure of a bimolecular human telomeric quadruplex, of the sequence d(TAGGGTTAGGG), in a complex with the quadruplex-binding ligand 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) to a resolution of 2.09 A. The DNA quadruplex topology is parallel-stranded with external double-chain-reversal propeller loops, consistent with previous structural determinations. The porphyrin molecules bind by stacking onto the TTA nucleotides, either as part of the external loop structure or at the 5' region of the stacked quadruplex. This involves stacked on hydrogen-bonded base pairs, formed from those nucleotides not involved in the formation of G-tetrads, and there are thus no direct ligand interactions with G-tetrads. This is in accord with the relative nonselectivity by TMPyP4 for quadruplex DNAs compared to duplex DNA. Porphyrin binding is achieved by remodeling of loops compared to the ligand-free structures. Implications for the design of quadruplex-binding ligands are discussed, together with a model for the formation of anaphase bridges, which are observed following cellular treatment with TMPyP4.