Crystal structure of DNA-bound Co(III)-bleomycin B2:: Insights on intercalation and minor groove binding
Crystal structure of DNA-bound Co(III)-bleomycin B2:: Insights on intercalation and minor groove binding
复制标题
DOI：
10.1073/pnas.0708143105
复制
发表时间：
2008-04-01
影响因子：
11.1
通讯作者：
Georgiadis, Millie M.
中科院分区：
文献类型：
--
作者：
Goodwin, Kristie D.;Lewis, Mark A.;Georgiadis, Millie M.
博来霉素是一类被广泛研究的切割复杂DNA的天然产物，用于治疗各种癌症。自其首次分离以来，博来霉素为开发和发现额外的DNA裂解化疗剂提供了范例。博来霉素由通过甲基戊酸-Thr接头连接到联噻唑/C-末端尾部的双硫醚修饰的金属结合结构域组成，并且在氧活化后通过在5 '-GT/C位点处对双链体DNA进行位点选择性切割来诱导DNA损伤。在这里，我们提出了两种不同的5 '-GT含有寡核苷酸在存在和不存在结合的Co（III）-博来霉素B-2的晶体结构。我们研究的几个发现影响了目前博来霉素与DNA结合的观点。首先，我们报告说，双噻唑插入在两个不同的模式，并可以这样做独立的良好有序的小沟结合的金属结合/二糖结构域。其次，在我们的结构中的Co（III）-配位赤道配体包括咪唑，组氨酸酰胺，嘧啶N1，和β氨基丙氨酸的仲胺，而伯胺作为轴向配体。第三，Co（III）-博来霉素的小沟结合涉及金属结合结构域和二糖与DNA的直接氢键相互作用。最后，与Co（III）配位的氢过氧化物配体的建模表明，它理想地定位于C4 '-H提取的起始。
Bleomycins constitute a widely studied class of complex DNA cleaving natural products that are used to treat various cancers. Since their first isolation, the bleomycins have provided a paradigm for the development and discovery of additional DNA-cleaving chemotherapeutic agents. The bleomycins consist of a disaccharide-modified metal-binding domain connected to a bithiazole/C-terminal tail via a methylvalerate-Thr linker and induce DNA damage after oxygen activation through site-selective cleavage of duplex DNA at 5'-GT/C sites. Here, we present crystal structures of two different 5'-GT containing oligonucleotides in both the presence and absence of bound Co(III)-bleomycin B-2. Several findings from our studies impact the current view of bleomycin binding to DNA. First, we report that the bithiazole intercalates in two distinct modes and can do so independently of well ordered minor groove binding of the metal binding/disaccharide domains. Second, the Co(III)-coordinating equatorial ligands in our structure include the imidazole, histidine amide, pyrimidine N1, and the secondary amine of the beta aminoalanine, whereas the primary amine acts as an axial ligand. Third, minor groove binding of Co(Ill)-bleomycin involves direct hydrogen bonding interactions of the metal binding domain and disaccharide with the DNA. Finally, modeling of a hydroperoxide ligand coordinated to Co(III) suggests that it is ideally positioned for initiation of C4'-H abstraction.