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

Kai-Bo Wang (), Yushuang Liu, Jinzhu Li, Chengmei Xiao, Yingying Wang, Wei Gu, Yipu Li, Yuan-Zheng Xia, Tingdong Yan, Ming-Hua Yang and Ling-Yi Kong ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33761-4

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