Solution structures of multiple G-quadruplex complexes induced by a platinum(II)-based tripod reveal dynamic binding

Wenting Liu, Yi-Fang Zhong, Liu-Yi Liu, Chu-Tong Shen, Wenjuan Zeng, Fuyi Wang, Danzhou Yang () and Zong-Wan Mao ()
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Wenting Liu: Sun Yat-Sen University
Yi-Fang Zhong: Sun Yat-Sen University
Liu-Yi Liu: Sun Yat-Sen University
Chu-Tong Shen: Sun Yat-Sen University
Wenjuan Zeng: Chinese Academy of Sciences
Fuyi Wang: Chinese Academy of Sciences
Danzhou Yang: Purdue University
Zong-Wan Mao: Sun Yat-Sen University

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract DNA G-quadruplexes are not only attractive drug targets for cancer therapeutics, but also have important applications in supramolecular assembly. Here, we report a platinum(II)-based tripod (Pt-tripod) specifically binds the biological relevant hybrid-1 human telomeric G-quadruplex (Tel26), and strongly inhibits telomerase activity. Further investigations illustrate Pt-tripod induces the formation of monomeric and multimeric Pt-tripod‒Tel26 complex structures in solution. We solve the 1:1 and the unique dimeric 4:2 Pt-tripod–Tel26 complex structures by NMR. The structures indicate preferential binding of Pt-tripod to the 5ʹ-end of Tel26 at a low Pt-tripod/Tel26 ratio of 0–1.0. After adding more Pt-tripod, the Pt-tripod binds the 3ʹ-end of Tel26, unexpectedly inducing a unique dimeric 4:2 structure interlocked by an A:A non-canonical pair at the 3ʹ-end. Our structures provide a structural basis for understanding the dynamic binding of small molecules with G-quadruplex and DNA damage mechanisms, and insights into the recognition and assembly of higher-order G-quadruplexes.

Date: 2018
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DOI: 10.1038/s41467-018-05810-4

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