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

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. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. Herein, the authors report the NMR solution structures of a bulge-containing KRAS-G4 that bound to two small molecules. The study provides molecular details of ligand interactions with KRAS-G4 and contributes insight into the design of specific KRAS-G4-interactive drugs.