School of Physical and Mathematical Sciences , Nanyang Technological University , Singapore 637371 , Singapore.
Laboratoire de Biologie et de Pharmacologie Appliquée , CNRS UMR 8113 , Ecole Normale Supérieure Paris-Saclay , Cachan 94235 , France.
J Am Chem Soc. 2019 Nov 13;141(45):18038-18047. doi: 10.1021/jacs.9b05642. Epub 2019 Oct 29.
Cyclic dinucleotides have emerged as important secondary messengers and cell signaling molecules that regulate several cell responses. A guanine-deficit G-quadruplex structure formation by a sequence containing (4 - 1) guanines, denoting the number of G-tetrad layers, was previously reported. Here, a (4 - 1) G-quadruplex structure is shown to be capable of binding guanine-containing dinucleotides in micromolar affinity. The guanine base of the dinucleotides interacts with a vacant G-triad, forming four additional Hoogsteen hydrogen bonds to complete a G-tetrad. Solution structures of two complexes, both comprised of a (4 - 1) G-quadruplex structure, one bound to a linear dinucleotide (d(AG)) and the other to a cyclic dinucleotide (cGAMP), are solved using NMR spectroscopy. The latter suggests sufficiently strong interaction between the guanine base of the dinucleotide and the vacant G-triad, which acts as an anchor point of binding. The binding interfaces from the two solution structures provide useful information for specific ligand design. The results also infer that other guanine-containing metabolites of a similar size have the capability of binding G-quadruplexes, potentially affecting the expression of the metabolites and functionality of the bound G-quadruplexes.
环二核苷酸已成为重要的第二信使和细胞信号分子，调节多种细胞反应。先前报道了由含有（4-1）个鸟嘌呤的序列形成鸟嘌呤缺乏的 G-四链体结构，其中 4-1 表示 G-四联体层的数量。此处显示，（4-1）G-四链体结构能够以微摩尔亲和力结合含鸟嘌呤的二核苷酸。二核苷酸的鸟嘌呤碱基与空的 G-三联体相互作用，形成另外四个 Hoogsteen 氢键，以完成 G-四联体。使用 NMR 光谱法解决了两个复合物的溶液结构，均由（4-1）G-四链体结构组成，一个与线性二核苷酸（d（AG））结合，另一个与环状二核苷酸（cGAMP）结合。后者表明二核苷酸的鸟嘌呤碱基与空的 G-三联体之间存在足够强的相互作用，后者充当结合的锚定点。来自两个溶液结构的结合界面为特定配体设计提供了有用信息。结果还推断，具有类似大小的其他含鸟嘌呤的代谢物具有结合 G-四链体的能力，可能影响代谢物的表达和结合的 G-四链体的功能。
