Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex.
Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex.
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DOI：
10.1038/s41467-018-06315-w
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发表时间：
2018-10-12
影响因子：
16.6
通讯作者：
Schneekloth JS Jr
中科院分区：
文献类型：
--
作者：
Calabrese DR;Chen X;Leon EC;Gaikwad SM;Phyo Z;Hewitt WM;Alden S;Hilimire TA;He F;Michalowski AM;Simmons JK;Saunders LB;Zhang S;Connors D;Walters KJ;Mock BA;Schneekloth JS Jr
G-四链体 (G4) 是非常规 DNA 结构，经常出现在癌基因（例如 MYC）的启动子区域，并调节基因表达。尽管 G4 是有吸引力的治疗靶点，但能够区分不同 G4 结构的配体很少见。在这里，我们描述了 DC-34，这是一种通过 G4 依赖性机制有效下调癌细胞中 MYC 转录的小分子。 DC-34 对 MYC 的抑制作用明显强于其他 G4 驱动基因。我们利用化学、生物物理、生物学和结构研究来证明 MYC G4 识别的分子原理。我们通过核磁共振波谱解析了 MYC G4 与 DC-34 复合物的结构，并说明了负责亲和力和选择性的特定接触。 DC-34 的修饰揭示了 G4 亲和力、生物活性所需的特征，并验证了衍生的 NMR 结构。这项工作推进了四联体相互作用小分子的设计，以控制癌症等治疗领域的基因表达。用小分子靶向非编码核酸是化学生物学和药物发现中的一个重要且重大的挑战。在这里，作者描述了 DC-34（一种小分子，它表现出与特定 G4 结构的选择性结合），并为其选择性提供了结构基础
G-quadruplexes (G4s) are noncanonical DNA structures that frequently occur in the promoter regions of oncogenes, such as MYC, and regulate gene expression. Although G4s are attractive therapeutic targets, ligands capable of discriminating between different G4 structures are rare. Here, we describe DC-34, a small molecule that potently downregulates MYC transcription in cancer cells by a G4-dependent mechanism. Inhibition by DC-34 is significantly greater for MYC than other G4-driven genes. We use chemical, biophysical, biological, and structural studies to demonstrate a molecular rationale for the recognition of the MYC G4. We solve the structure of the MYC G4 in complex with DC-34 by NMR spectroscopy and illustrate specific contacts responsible for affinity and selectivity. Modification of DC-34 reveals features required for G4 affinity, biological activity, and validates the derived NMR structure. This work advances the design of quadruplex-interacting small molecules to control gene expression in therapeutic areas such as cancer. Targeting noncoding nucleic acids with small molecules represents an important and significant challenge in chemical biology and drug discovery. Here the authors characterize DC-34, a small molecule that exhibits selective binding to specific G4 structures, and provide a structural basis for its selectivity
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影响因子：
46.9
作者：
Chambers, Vicki S.;Marsico, Giovanni;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
影响因子：
7.3
作者：
Boddupally, Peda V. L.;Hahn, Seongmin;Beman, Cristina;De, Biswanath;Brooks, Tracy A.;Gokhale, Vijay;Hurley, Laurence H.
通讯作者：
Hurley, Laurence H.
DOI：
10.3390/molecules181012368
发表时间：
2013-10-08
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Bidzinska J;Cimino-Reale G;Zaffaroni N;Folini M
通讯作者：
Folini M
影响因子：
15
作者：
Dai, Jixun;Carver, Megan;Hurley, Laurence H.;Yang, Danzhou
通讯作者：
Yang, Danzhou
DOI：
10.3390/molecules181012751
发表时间：
2013-10-15
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Cui J;Waltman P;Le VH;Lewis EA
通讯作者：
Lewis EA