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; Zong Wan Mao

doi:10.1038/s41467-018-05810-4

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, Zong Wan Mao

Pharmacology and Toxicology

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

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.

Original language	English (US)
Article number	3496
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05810-4
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-018-05810-4

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@article{e213d39e5ee1416199fb89e5992a3a77,

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

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.",

author = "Wenting Liu and Zhong, {Yi Fang} and Liu, {Liu Yi} and Shen, {Chu Tong} and Wenjuan Zeng and Fuyi Wang and Danzhou Yang and Mao, {Zong Wan}",

note = "Funding Information: This work was funded by the 973 program (Nos. 2014CB845604 and 2015CB856301), the National Science Foundation of China (Nos. 21837006 and 21572282), the Ministry of Education of China (IRT-17R111), Science and Technology Planning Project of Guangdong Province (Nos. 2013B051000047 and 207999), the Fundamental Research Funds for the Central Universities, and the US National Institutes of Health (R01CA177585 (D.Y.), and P30CA023168 (Purdue Center for Cancer Research)). We thank Professor Hai-Bin Luo (School of Pharmaceutical Sciences, Sun Yat-Sen University) for his support with the molecular dynamics simulation. We thank Qian Hu (School of Life Science, Sun Yat-Sen University) for his help with the TRAP-LIG experiment. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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month = dec,

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doi = "10.1038/s41467-018-05810-4",

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T1 - Solution structures of multiple G-quadruplex complexes induced by a platinum(II)-based tripod reveal dynamic binding

AU - Liu, Wenting

AU - Zhong, Yi Fang

AU - Liu, Liu Yi

AU - Shen, Chu Tong

AU - Zeng, Wenjuan

AU - Wang, Fuyi

AU - Yang, Danzhou

AU - Mao, Zong Wan

N1 - Funding Information: This work was funded by the 973 program (Nos. 2014CB845604 and 2015CB856301), the National Science Foundation of China (Nos. 21837006 and 21572282), the Ministry of Education of China (IRT-17R111), Science and Technology Planning Project of Guangdong Province (Nos. 2013B051000047 and 207999), the Fundamental Research Funds for the Central Universities, and the US National Institutes of Health (R01CA177585 (D.Y.), and P30CA023168 (Purdue Center for Cancer Research)). We thank Professor Hai-Bin Luo (School of Pharmaceutical Sciences, Sun Yat-Sen University) for his support with the molecular dynamics simulation. We thank Qian Hu (School of Life Science, Sun Yat-Sen University) for his help with the TRAP-LIG experiment. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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

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