连续结合 MYC G-四链体的铂化合物的溶液结构和效应。

Solution structures and effects of a platinum compound successively bound MYC G-quadruplex.

机构信息

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, IGCME, GBRCE for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou 510006, China.

Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue Center for Cancer Research, Department of Chemistry, and Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA.

出版信息

Nucleic Acids Res. 2024 Sep 9;52(16):9397-9406. doi: 10.1093/nar/gkae649.

DOI:10.1093/nar/gkae649

PMID:39077944

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11381319/

Abstract

G-quadruplex (G4) structures play integral roles in modulating biological functions and can be regulated by small molecules. The MYC gene is critical during tumor initiation and malignant progression, in which G4 acts as an important modulation motif. Herein, we reported the MYC promoter G4 recognized by a platinum(II) compound Pt-phen. Two Pt-phen-MYC G4 complex structures in 5 mM K+ were determined by NMR. The Pt-phen first strongly binds the 3'-end of MYC G4 to form a 1:1 3'-end binding complex and then binds 5'-end to form a 2:1 complex with more Pt-phen. In the complexes, the Pt-phen molecules are well-defined and stack over four bases at the G-tetrad for a highly extensive π-π interaction, with the Pt atom aligning with the center of the G-tetrad. The flanking residues were observed to rearrange and cover on top of Pt-phen to stabilize the whole complex. We further demonstrated that Pt-phen targets G4 DNA in living cells and represses MYC gene expression in cancer cells. Our work elucidated the structural basis of ligand binding to MYC promoter G4. The platinum compound bound G4 includes multiple complexes formation, providing insights into the design of metal ligands targeting oncogene G4 DNA.

摘要

G-四链体（G4）结构在调节生物功能方面发挥着重要作用，可以被小分子调控。MYC 基因在肿瘤起始和恶性进展中至关重要，其中 G4 作为一个重要的调节基序。在此，我们报道了 MYC 启动子 G4 被铂(II)配合物 Pt-phen 识别。通过 NMR 确定了在 5 mM K+ 下两种 Pt-phen-MYC G4 复合物的结构。Pt-phen 首先强烈结合 MYC G4 的 3'-末端，形成 1:1 的 3'-末端结合复合物，然后结合 5'-末端，与更多的 Pt-phen 形成 2:1 复合物。在复合物中，Pt-phen 分子被很好地定义，并在 G-四联体的四个碱基上堆积，形成高度扩展的π-π相互作用，Pt 原子与 G-四联体的中心对齐。侧翼残基被观察到重新排列并覆盖在 Pt-phen 上，以稳定整个复合物。我们进一步证明，Pt-phen 靶向活细胞中的 G4 DNA，并抑制癌细胞中 MYC 基因的表达。我们的工作阐明了配体与 MYC 启动子 G4 结合的结构基础。结合 G4 的铂化合物包含多种复合物的形成，为设计针对致癌基因 G4 DNA 的金属配体提供了思路。