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Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine

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  • Kai-Bo Wang

    (China Pharmaceutical University)

  • Yushuang Liu

    (China Pharmaceutical University)

  • Jinzhu Li

    (China Pharmaceutical University)

  • Chengmei Xiao

    (China Pharmaceutical University)

  • Yingying Wang

    (China Pharmaceutical University)

  • Wei Gu

    (Shanghai University)

  • Yipu Li

    (China Pharmaceutical University)

  • Yuan-Zheng Xia

    (China Pharmaceutical University)

  • Tingdong Yan

    (Shanghai University)

  • Ming-Hua Yang

    (China Pharmaceutical University)

  • Ling-Yi Kong

    (China Pharmaceutical University)

Abstract

KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a “quasi-triad plane” that stacks over the two external G-tetrads. The binding involves both π-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS-G4 and is beneficial for the design of specific KRAS-G4-interactive drugs.

Suggested Citation

  • Kai-Bo Wang & Yushuang Liu & Jinzhu Li & Chengmei Xiao & Yingying Wang & Wei Gu & Yipu Li & Yuan-Zheng Xia & Tingdong Yan & Ming-Hua Yang & Ling-Yi Kong, 2022. "Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33761-4
    DOI: 10.1038/s41467-022-33761-4
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    References listed on IDEAS

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    1. Jing Tu & Mengqin Duan & Wenli Liu & Na Lu & Yue Zhou & Xiao Sun & Zuhong Lu, 2021. "Direct genome-wide identification of G-quadruplex structures by whole-genome resequencing," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    2. Peter A. Summers & Benjamin W. Lewis & Jorge Gonzalez-Garcia & Rosa M. Porreca & Aaron H. M. Lim & Paolo Cadinu & Nerea Martin-Pintado & David J. Mann & Joshua B. Edel & Jean Baptiste Vannier & Marina, 2021. "Visualising G-quadruplex DNA dynamics in live cells by fluorescence lifetime imaging microscopy," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Jude Canon & Karen Rex & Anne Y. Saiki & Christopher Mohr & Keegan Cooke & Dhanashri Bagal & Kevin Gaida & Tyler Holt & Charles G. Knutson & Neelima Koppada & Brian A. Lanman & Jonathan Werner & Aaron, 2019. "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity," Nature, Nature, vol. 575(7781), pages 217-223, November.
    4. David R. Calabrese & Xiang Chen & Elena C. Leon & Snehal M. Gaikwad & Zaw Phyo & William M. Hewitt & Stephanie Alden & Thomas A. Hilimire & Fahu He & Aleksandra M. Michalowski & John K. Simmons & Lind, 2018. "Chemical and structural studies provide a mechanistic basis for recognition of the MYC G-quadruplex," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    5. Wenting Liu & Yi-Fang Zhong & Liu-Yi Liu & Chu-Tong Shen & Wenjuan Zeng & Fuyi Wang & Danzhou Yang & Zong-Wan Mao, 2018. "Solution structures of multiple G-quadruplex complexes induced by a platinum(II)-based tripod reveal dynamic binding," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    6. Jonathan M. Ostrem & Ulf Peters & Martin L. Sos & James A. Wells & Kevan M. Shokat, 2013. "K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions," Nature, Nature, vol. 503(7477), pages 548-551, November.
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