Crystal structure of the [Mg2+-(chromomycin A3)2]-d(TTGGCCAA)2 complex reveals GGCC binding specificity of the drug dimer chelated by a metal ion
Crystal structure of the [Mg2+-(chromomycin A3)2]-d(TTGGCCAA)2 complex reveals GGCC binding specificity of the drug dimer chelated by a metal ion
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DOI：
10.1093/nar/gkh549
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发表时间：
2004-04-01
影响因子：
14.9
通讯作者：
Wang, AHJ
中科院分区：
文献类型：
--
作者：
Hou, MH;Robinson, H;Wang, AHJ
抗癌抗生素铬霉素A(3) （Chro）是一种DNA小槽结合药物，属于黄醛家族。Chro可能通过干扰复制和转录发挥其活性。铬形成二聚体，由二价金属离子介导，与富含G/ c的DNA结合。本文报道了基于螯合Co3+离子的多波长异常衍射（MAD）解决的第一个Chro与d(TTG GCCAA)(2) DNA双链结合的晶体结构。Mg2+配合物的结构随后在2.15埃分辨率下进行了细化，发现两个金属配位的二聚铬配合物在不对称单元中与八聚体DNA双链结合。金属离子与发色团（CPH）的O1和O9氧原子八面配位，两个水分子作为第五和第六配体。这两个配位的水分子与C5和C13碱基的氧原子成氢键。Chro二聚体结合在GGCC序列的小凹槽处并显著加宽。每个发色团的长轴沿着并堆叠在糖-磷酸主链上，两个附着的糖基团（环A/B和C/D/E）包裹在小槽上。DNA在这两个复合体中分别以30度和36度的角度缠绕。在Chro和DNA之间的6个g特异性氢键提供了GGCC序列的特异性。有趣的是，从圆二色性和晶体结构数据可以看出，DNA与Chro协同作用似乎是催化Co(NH3)(6)（3+）脱氨的有效模板。我们的结果为将来设计新的抗癌药物衍生物提供了有用的结构信息。
The anticancer antibiotic chromomycin A(3) (Chro) is a DNA minor groove binding drug belonging to the aureolic family. Chro likely exerts its activity by interfering with replication and transcription. Chro forms a dimer, mediated by a divalent metal ion, which binds to G/C-rich DNA. Herein we report the first crystal structure of Chro bound to d(TTG GCCAA)(2) DNA duplex solved by multiwavelength anomalous diffraction (MAD) based on the chelated Co3+ ion. The structure of the Mg2+ complex was subsequently refined at 2.15 Angstrom resolution, which revealed two complexes of metal-coordinated dimers of Chro bound to the octamer DNA duplex in the asymmetric unit. The metal ion is octahedrally coordinated to the O1 and O9 oxygen atoms of the chromophore (CPH), and two water molecules act as the fifth and sixth ligands. The two coordinated water molecules are hydrogen bonded to O2 atoms of C5 and C13 bases. The Chro dimer binds at and significantly widens the minor groove of the GGCC sequence. The long axis of each chromophore lies along and stacks over the sugar-phosphate backbone with the two attached saccharide moieties (rings A/B and C/D/E) wrapping across the minor groove. DNA is kinked by 30degrees and 36degrees in the two complexes, respectively. Six G-specific hydrogen bonds between Chro and DNA provide the GGCC sequence specificity. Interestingly, DNA in concert with Chro appears to act as an effective template to catalyze the deamination of Co(NH3)(6)(3+), as shown by circular dichroism and crystal structure data. Our results present useful structural information for designing new anticancer drug derivatives in the future.