Wang Y, Patel D J
Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Structure. 1993 Dec 15;1(4):263-82. doi: 10.1016/0969-2126(93)90015-9.
Repeats of Gn 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.
We have determined the three-dimensional solution structure of the human telomere sequence, d[AG3(T2AG3)3] in Na(+)-containing solution using a combined NMR, distance geometry and molecular dynamics approach (including relaxation matrix refinement). The sequence, which contains four AG3 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 that 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.
The availability of the d[AG3(T2AG3)3] solution structure containing four AG3 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.
在真核染色体末端，Gn序列的重复片段与相关结合蛋白一起被检测为单链悬垂。这种端粒序列与染色体末端的复制和维持有关。它们也可能在减数分裂和有丝分裂过程中介导染色体的组织和关联。
我们使用核磁共振、距离几何和分子动力学方法（包括弛豫矩阵精修），确定了含钠溶液中人类端粒序列d[AG3(T2AG3)3]的三维溶液结构。该序列包含四个AG3重复片段，分子内折叠成一个由三个堆叠的G-四联体稳定的G-四链体，这些G-四联体由两个侧向环和一个中央对角环连接。在形成的四个凹槽中，一个宽，两个中等宽度，一个窄。相邻G-G-G片段的平行排列产生了两个中等宽度的凹槽，而反平行排列导致一个宽凹槽和一个窄凹槽。四个腺嘌呤中的三个堆叠在相邻G-四联体的顶部，而大多数胸腺嘧啶呈现多种构象。
含有四个AG3人类端粒重复片段的d[AG3(T2AG)3]溶液结构的可得性，应有助于合理设计能特异性且亲和地识别并结合G-四链体各个凹槽以及包含对角环和侧向环的任一端的配体。此类配体可调节折叠的G-四链体结构与其未折叠的伸展对应物之间的平衡。
