Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Nat Chem. 2012 Jun 10;4(8):615-20. doi: 10.1038/nchem.1375.
DNA mismatches represent a novel target in the development of diagnostics and therapeutics for cancer, because deficiencies in DNA mismatch repair are implicated in cancers, and cells that are repair-deficient show a high frequency of mismatches. Metal complexes with bulky intercalating ligands serve as probes for DNA mismatches. Here, we report the high-resolution (0.92 Å) crystal structure of the ruthenium 'light switch' complex Δ-Ru(bpy)(2)dppz (bpy = 2,2'-bipyridine and dppz = dipyridophenazine), which is known to show luminescence on binding to duplex DNA, bound to both mismatched and well-matched sites in the oligonucleotide 5'-(dCGGAAATTACCG)(2)-3' (underline denotes AA mismatches). Two crystallographically independent views reveal that the complex binds mismatches through metalloinsertion, ejecting both mispaired adenosines. Additional ruthenium complexes are intercalated at well-matched sites, creating an array of complexes in the minor groove stabilized by stacking interactions between bpy ligands and extruded adenosines. This structure attests to the generality of metalloinsertion and metallointercalation as DNA binding modes.
DNA 错配代表了癌症诊断和治疗新的靶点，因为 DNA 错配修复缺陷与癌症有关，而且修复缺陷的细胞显示出较高的错配频率。具有大的嵌入配体的金属配合物可用作 DNA 错配的探针。在这里，我们报道了钌“光开关”配合物 Δ-Ru(bpy)(2)dppz（bpy=2,2'-联吡啶，dppz=二吡啶并吩嗪）的高分辨率（0.92 Å）晶体结构，已知该配合物在与双链 DNA 结合时会发出荧光，结合到寡核苷酸 5'-(dCGGAAATTACCG)(2)-3'（下划线表示 AA 错配）中的错配和完全匹配的位点。两个晶体学上独立的结构揭示了该配合物通过金属插入结合错配，将两个错配的腺嘌呤排出。额外的钌配合物在完全匹配的位点嵌入，通过 bpy 配体与伸出的腺嘌呤之间的堆积相互作用在小沟中稳定了一系列配合物。该结构证明了金属插入和金属嵌入作为 DNA 结合模式的普遍性。
