Phan Anh Tuân, Kuryavyi Vitaly, Burge Sarah, Neidle Stephen, Patel Dinshaw J
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Am Chem Soc. 2007 Apr 11;129(14):4386-92. doi: 10.1021/ja068739h. Epub 2007 Mar 16.
The c-kit oncogene is an important target in the treatment of gastrointestinal tumors. A potential approach to inhibition of the expression of this gene involves selective stabilization of G-quadruplex structures that may be induced to form in the c-kit promoter region. Here we report on the structure of an unprecedented intramolecular G-quadruplex formed by a G-rich sequence in the c-kit promoter in K+ solution. The structure represents a new folding topology with several unique features. Most strikingly, an isolated guanine is involved in G-tetrad core formation, despite the presence of four three-guanine tracts. There are four loops: two single-residue double-chain-reversal loops, a two-residue loop, and a five-residue stem-loop, which contain base-pairing alignments. This unique structural scaffold provides a highly specific platform for the future design of ligands specifically targeted to the promoter DNA of c-kit.
c-kit癌基因是胃肠道肿瘤治疗中的一个重要靶点。抑制该基因表达的一种潜在方法是选择性稳定可能在c-kit启动子区域诱导形成的G-四链体结构。在此，我们报道了在K+溶液中由c-kit启动子中的富含G的序列形成的前所未有的分子内G-四链体的结构。该结构代表了一种具有几个独特特征的新折叠拓扑。最引人注目的是，尽管存在四个三鸟嘌呤束，但一个孤立的鸟嘌呤参与了G-四联体核心的形成。有四个环：两个单残基双链反转环、一个双残基环和一个五残基茎环，它们包含碱基配对排列。这种独特的结构支架为未来设计专门靶向c-kit启动子DNA的配体提供了一个高度特异性的平台。
