SOLUTION STRUCTURE OF THE HUMAN TELOMERIC REPEAT D[AG(3)(T(2)AG(3))3] G-TETRAPLEX
SOLUTION STRUCTURE OF THE HUMAN TELOMERIC REPEAT D[AG(3)(T(2)AG(3))3] G-TETRAPLEX
复制标题
DOI：
10.1016/0969-2126(93)90015-9
复制
发表时间：
1993-12-15
期刊：
影响因子：
5.7
通讯作者：
PATEL, DJ
中科院分区：
文献类型：
--
作者：
WANG, Y;PATEL, DJ
背景：G，序列的重复被检测为真核染色体末端的单链突出端以及相关的结合蛋白。这种端粒序列与染色体末端的复制和维持有关。它们还可能在减数分裂和有丝分裂过程中介导染色体组织和关联。 结果：我们使用核磁共振、距离几何和分子动力学相结合的方法（包括松弛矩阵细化）确定了含 Na+ 溶液中人类端粒序列 d[AG(3)(T(2)AG(3))(3)] 的三维溶液结构。该序列包含四个 AG(3) 重复序列，在分子内折叠成由三个堆叠的 G-四联体稳定的 G-四联体，这三个堆叠的 G-四联体通过两个侧环和一个中心对角环连接。形成的四个凹槽中，一个是宽的，两个是中宽度的，一个是窄的。相邻的 G-G-G 段平行排列会产生两个中等宽度的凹槽，而反向平行排列则会产生一宽一窄的凹槽。四个腺嘌呤中的三个堆叠在相邻 G-四联体的顶部，而大多数胸腺嘧啶采样多种构象。结论：包含四个 AG(3) 人端粒重复的 d[AG(3)(T(2)AG(3))(3)] 溶液结构的可用性应允许合理设计配体，这些配体以特异性和亲和力识别和结合 G-四联体的各个凹槽，以及包含对角线和侧向的任一端循环。这种配体可以调节折叠的 G-四链体结构与其未折叠的延伸对应物之间的平衡。
Background: Repeats of G, sequences are detected as single strand overhangs at the ends of eukaryotic chromosomes together with associated binding proteins. Such telomere sequences have been implicated in the replication and maintenance of chromosomal termini. They may also mediate chromosomal organization and association during meiosis and mitosis.Results: We have determined the three-dimensional solution structure of the human telomere sequence, d[AG(3)(T(2)AG(3))(3)] in Na+-containing solution using a combined NMR, distance geometry and molecular dynamics approach (including relaxation matrix refinement). The sequence, which contains four AG(3) repeats, folds intramolecularly into a G-tetraplex stabilized by three stacked G-tetrads which are connected by two lateral loops and a central diagonal loop. Of the four grooves chat are formed, one is wide, two are of medium width and one is narrow. The alignment of adjacent G-G-G segments in parallel generates the two grooves of medium width whilst the antiparallel arrangement results in one wide and one narrow groove. Three of the four adenines stack on top of adjacent G-tetrads while the majority of the thymines sample multiple conformations.Conclusions: The availability of the d[AG(3)(T(2)AG(3))(3)] solution structure containing four AG(3) human telomeric repeats should permit the rational design of ligands that recognize and bind with specificity and affinity to the individual grooves of the G-tetraplex, as well as to either end containing the diagonal and lateral loops. Such ligands could modulate the equilibrium between folded G-tetraplex structures and their unfolded extended counterparts.