Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 9, Ljubljana, Slovenia.
EN- FIST Centre of Excellence, Trg OF 13, Ljubljana, Slovenia.
Angew Chem Int Ed Engl. 2018 Nov 19;57(47):15395-15399. doi: 10.1002/anie.201809328. Epub 2018 Oct 17.
A G-rich sequence found in the regulatory region of the RANKL gene, which is associated with homeostasis of bone metabolism, folds into a two-quartet basket-type G-quadruplex stabilized by A⋅G⋅A and G⋅G⋅G base-triads. Perusal of local structural features together with G/A-to-T modifications uncovered the critical role of A5 for the formation of a distinct antiparallel two-quartet topology and not the three-quartet topology that would be expected based on the sequence with four GGG-tracts alone. The structural changes induced by the A5-to-T5 modification include a switch in orientation and relative positions of G-strands that together with anti to syn reorientation of G12 provide insights into the complexity of the interactions that influence the folding of G-rich DNA. Understanding the impact of loop residues on the stability and formation of G-quadruplexes advances our knowledge and ability to predict structures adopted by G-rich sequences, which are involved in regulatory mechanisms in the cell, and may also facilitate drug design.
在 RANKL 基因的调控区域中发现了一个富含 G 的序列，该序列与骨代谢的动态平衡有关，它折叠成一个由 A⋅G⋅A 和 G⋅G⋅G 碱基三联体稳定的四联体篮式 G-四链体。对局部结构特征的研究以及 G/A 到 T 的修饰揭示了 A5 对于形成独特的反平行四联体拓扑结构的关键作用，而不是基于仅含有四个 GGG-链的序列所预期的四联体拓扑结构。A5 到 T5 修饰所诱导的结构变化包括 G-链取向和相对位置的切换，G12 的反式到顺式的重新取向提供了对影响富含 G 的 DNA 折叠的相互作用复杂性的深入了解。了解环残基对 G-四链体稳定性和形成的影响，可提高我们对参与细胞调控机制的富含 G 序列的结构的认识和预测能力，并可能有助于药物设计。
