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Prof. Zong-Wan Mao’s group at School of Chemistry determined the NMR structures of G-quadruplex complexes with platinum(II)-based tripod

Last updated :2018-10-12

Source: School of Chemistry
Written by: School of Chemistry
Edited by: Wang Dongmei

DNA guanine-rich sequences can form non-canonical secondary structures known as G-quadruplexes. It has been suggested that DNA G-quadruplexes are involved in several key biological processes and various cancer and human genetic diseases. Such DNA secondary structures have attracted great interest nowadays due to the increasing evidence of their significant biological role, and have been developed as novel targets for anticancer drug development. Moreover, G-quadruplexes have important applications in various fields such as nanotechnology and assembling chemistry. The structure of DNA G-quadruplexes is polymorphic. Complete identification of the G-quadruplex structures and dynamics could provide fundamental insights for us to understand their existence and function in nature. And molecular level binding details of small molecule interactions with G-quadruplex DNA targets are essential for investigating the molecular mechanisms and instructive for structure-based rational drug design. Among the experimental techniques for studying G-quadruplexes, NMR spectroscopy has been used to obtain atomic-resolution G-quadruplex structures and investigate dynamics and interactions of G-quadruplexes.

The dynamic binding of the Pt-tripod and the human telomeric G-quadruplex DNA.
 
Professor Zong-Wan Mao from School of Chemistry at Sun Yat-sen University have developed a photosensitive platinum(II)-based tripods (Pt-tripod) and exhibited highly promising DNA-targeted photodynamic therapy anticancer activity both in vitro and in vivo (Chem. Eur. J., 2017, 23, 16442–16446). Mechanistic investigation revealed that under light irradiation, the Pt-tripod rapidly damaged DNA, including G-quadruplex DNA. On the basis of previous studies, professor Zong-Wan Mao’s research group has made a breakthrough in the determination of NMR structure for the complex of Pt-tripod and G-quadruplex DNA. The research group found that the Pt-tripod can specifically recognizes the biological relevant hybrid-1 human telomeric G-quadruplex (Tel26), and strongly inhibits telomerase activity. They explored the dynamic binding of Pt-tripod with Tel26 G-quadruplex by using NMR method. Interestingly, NMR studies showed the Pt-tripod gradually induces the formation of multiple Pt-tripod–G-quadruplex complex structures in solution, including monomeric, dimeric and multimeric complex structures. Unprecedentedly, the group solved the 1:1 and the first dimeric 4:2 Pt-tripod–Tel26 complex structures by NMR. The structures provide a significant structural basis for understanding the dynamic binding of small molecules with G-quadruplex and DNA damage mechanisms, and new insights into the recognition and assembly of higher-order G-quadruplexes.

This work has been published in Nature Communications (Wenting Liu, Yi-Fang Zhong, Liu-Yi Liu, Chu-Tong Shen, Wenjuan Zeng, Fuyi Wang, Danzhou Yang*and Zong-Wan Mao*. Solution structures of multiple G-quadruplex complexes induced by a platinum(II)-based tripod reveal dynamic binding. Nat. Commun., 2018, 9: 3496. | DOI: 10.1038/s41467-018-05810-4). This work was supported by the National Natural Science Foundation of China, the 973 program, the Ministry of Education of China, and the Natural Science Foundation of Guangdong Province.

Article link: https://www.nature.com/articles/s41467-018-05810-4