Phan Anh Tuân, Kuryavyi Vitaly, Gaw Hai Yan, Patel Dinshaw J
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Nat Chem Biol. 2005 Aug;1(3):167-73. doi: 10.1038/nchembio723. Epub 2005 Jul 17.
It has been widely accepted that DNA can adopt other biologically relevant structures beside the Watson-Crick double helix. One recent important example is the guanine-quadruplex (G-quadruplex) structure formed by guanine tracts found in the MYC (or c-myc) promoter region, which regulates the transcription of the MYC oncogene. Stabilization of this G-quadruplex by ligands, such as the cationic porphyrin TMPyP4, decreases the transcriptional level of MYC. Here, we report the first structure of a DNA fragment containing five guanine tracts from this region. An unusual G-quadruplex fold, which was derived from NMR restraints using unambiguous model-independent resonance assignment approaches, involves a core of three stacked guanine tetrads formed by four parallel guanine tracts with all anti guanines and a snapback 3'-end syn guanine. We have determined the structure of the complex formed between this G-quadruplex and TMPyP4. This structural information, combined with details of small-molecule interaction, provides a platform for the design of anticancer drugs targeting multi-guanine-tract sequences that are found in the MYC and other oncogenic promoters, as well as in telomeres.
人们普遍认为，除了沃森-克里克双螺旋结构外，DNA还能形成其他与生物学相关的结构。最近一个重要的例子是在MYC（或c-myc）启动子区域发现的鸟嘌呤序列形成的鸟嘌呤四链体（G-四链体）结构，该区域调控MYC癌基因的转录。通过配体（如阳离子卟啉TMPyP4）使这种G-四链体稳定，可降低MYC的转录水平。在此，我们报道了来自该区域的包含五个鸟嘌呤序列的DNA片段的首个结构。一种不寻常的G-四链体折叠结构，它是使用明确的与模型无关的共振归属方法从NMR限制条件推导出来的，其核心由四个平行鸟嘌呤序列形成的三个堆叠的鸟嘌呤四联结构成，所有鸟嘌呤均为反式构象，且3'-端有一个回折的顺式鸟嘌呤。我们已经确定了该G-四链体与TMPyP4形成的复合物的结构。这些结构信息，结合小分子相互作用的细节，为设计靶向存在于MYC和其他致癌启动子以及端粒中的多鸟嘌呤序列的抗癌药物提供了一个平台。
