Phan Anh Tuân, Luu Kim Ngoc, Patel Dinshaw J
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Nucleic Acids Res. 2006;34(19):5715-9. doi: 10.1093/nar/gkl726. Epub 2006 Oct 12.
Intramolecular G-quadruplexes formed by the human telomeric G-rich strand are promising anticancer targets. Here we show that four-repeat human telomeric DNA sequences can adopt two different intramolecular G-quadruplex folds in K+ solution. The two structures contain the (3+1) G-tetrad core, in which three G-tracts are oriented in one direction and the fourth in the opposite direction, with one double-chain-reversal and two edgewise loops, but involve different loop arrangements. This result indicates the robustness of the (3+1) core G-quadruplex topology, thereby suggesting it as an important platform for structure-based drug design. Our data also support the view that multiple human telomeric G-quadruplex conformations coexist in K+ solution. Furthermore, even small changes to flanking sequences can perturb the equilibrium between different coexisting G-quadruplex forms.
由人类富含G的端粒链形成的分子内G-四链体是很有前景的抗癌靶点。我们在此表明，四重复的人类端粒DNA序列在K+溶液中可呈现两种不同的分子内G-四链体折叠结构。这两种结构都包含(3+1) G-四联体核心，其中三条G链同向排列，第四条反向排列，带有一个双链反转和两个边缘环，但环的排列方式不同。这一结果表明了(3+1)核心G-四链体拓扑结构的稳定性，从而表明它是基于结构的药物设计的重要平台。我们的数据还支持这样一种观点，即在K+溶液中多种人类端粒G-四链体构象共存。此外，即使侧翼序列发生微小变化也会扰乱不同共存G-四链体形式之间的平衡。
