2. Academic Validation
  3. Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine

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

  • Nat Commun. 2022 Oct 12;13(1):6016. doi: 10.1038/s41467-022-33761-4.
Kai-Bo Wang # 1,  Yushuang Liu # 2,  Jinzhu Li 2,  Chengmei Xiao 2,  Yingying Wang 2,  Wei Gu 3,  Yipu Li 2,  Yuan-Zheng Xia 2,  Tingdong Yan 3,  Ming-Hua Yang 2,  Ling-Yi Kong 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. kbwang@cpu.edu.cn.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 School of Life Sciences, Shanghai University, Shanghai, 200444, China.
  • 4 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China. cpu_lykong@126.com.
  • # Contributed equally.
PMID: 36224201 DOI: 10.1038/s41467-022-33761-4
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.

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