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首页> 外文期刊>Biochemistry >Binding of a Macrocyclic Bisacridine and Ametantrone to CGTACG Involves Similar Unusual Intercalation Platforms
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Binding of a Macrocyclic Bisacridine and Ametantrone to CGTACG Involves Similar Unusual Intercalation Platforms

机译：大环比沙丁啶和金刚烷酮与CGTACG的结合涉及相似的异常插入平台

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The binding of a macrocyclic bisacridine and an antitumor intercalator ametantrone to DNA has been studied. We carried out X-ray diffraction analyses of the complexes between both intercalators and CGTACG. We have determined the crystal structure, by the multiple-wavelength anomalous diffraction (MAD) method,of bisacridine complexes with CGTA[br~5C]G at 1.8 A resolution. The refined native crystal structure at 1.1 A resolution (space group C222, a=29.58 A, b=54.04 A, c=40.22 A, and R-factor=0.163) revealed that only one acridine of the bisacridine drug binds at the C5pG6 step of the DNA, with the otehr acridine plus both linkers completely disordered. Surprisingly,both terminal G.C base pairs are unraveled. The C1 nucleotide is disordered,and the G2 base is bridged to its own phosphate P2 through a hydrated Co~(2+) ion. G12 is swung toward the minor groove with its base stacked over the backbone. The C7 nucleotide is flipped away from the duplex part and base paired to a 2-fold symmetry-related G6~*. The central four base pairs abdopt the B-DNA conformation. An unusual intercalator platform is formed by bringing four complexes together (involving the 222 symmetry) such that teh intercalator cavity is flanked by two sets of G.C base pairs (i.e., C5.G8 and G6.C7~*) on each side, joined together by G6.G8~8 tertiary base pairing interactions. In the bisacridine-CGTACG complex, the intercalation platform is intercalated with two acridines, whereas in the ametantrone-CGTACG complex, only one ametantrone is bound. NMR titration of the bisacridine to AACGATCGTT suggests that the bisacridine prefers to bridge more than one DNA duplex by intercalating each acridine to different duplexes. The results may be relevant in understanding binding of certain intercalators to DNA structure associated with the quadrulet helix and Holliday junction.
机译：已经研究了大环双ac啶和抗肿瘤嵌入剂金刚烷酮与DNA的结合。我们对嵌入剂和CGTACG之间的复合物进行了X射线衍射分析。我们通过多波长异常衍射（MAD）方法确定了比沙丁啶与CGTA [br〜5C] G的1.8 A分辨率的晶体结构。在1.1 A分辨率下（空间群C222，a = 29.58 A，b = 54.04 A，c = 40.22 A，R-factor = 0.163）的精制天然晶体结构显示，比沙r啶药物中只有一个a啶在C5pG6步骤结合DNA，其中啶啶加上两个接头完全无序。出乎意料的是，这两个末端G.C碱基对均未阐明。 C1核苷酸无序，G2碱基通过水合的Co〜（2+）离子桥接至其自身的磷酸酯P2。 G12朝次要槽摆动，其底部堆叠在主干上。将C7核苷酸从双链体部分上翻转下来，并与2倍对称相关的G6〜*碱基配对。中心的四个碱基对采用B-DNA构象。一个不寻常的嵌入剂平台是通过将四个复合体放在一起（涉及222对称性）而形成的，这样嵌入剂腔的两侧是两侧的两组GC碱基对（即C5.G8和G6.C7〜*）连接在一起通过G6.G8〜8三级碱基配对相互作用。在双ac啶-CGTACG复合物中，插入平台插入有两个a啶，而在金刚烷酮-CGTACG复合物中，仅结合一个金刚烷酮。对双ac啶的NMR滴定至AACGATCGTT表明，双bis啶更倾向于通过将每个a啶插入不同的双链体来桥接多个DNA双链体。该结果可能与理解某些嵌入剂与四链螺旋和霍利迪连接的DNA结构的结合有关。

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