Kirsten rat sarcoma virus mRNA G-quadruplex (KRAS mRNA G4)

The Kirsten rat sarcoma virus mRNA G-quadruplex (KRAS mRNA G4) is a non-canonical secondary structure located within the 5'-untranslated region (5'-UTR) of the KRAS messenger RNA. This structure forms from guanine-rich sequences that fold into four-stranded arrangements stabilized by Hoogsteen hydrogen bonding (Cogoi & Xodo, 2006, Biochemistry). In its folded state, the G-quadruplex acts as a physical barrier to the 40S ribosomal subunit during scanning, effectively suppressing the translation of the KRAS protein (Cogoi et al., 2010, Journal of Medicinal Chemistry). Because KRAS is a major oncogene frequently mutated in pancreatic, colorectal, and lung cancers, this G4 structure represents a significant therapeutic target for downregulating KRAS expression at the pre-translational level (Prior et al., 2012, Cancer Research). Small molecules known as G4 ligands can bind and stabilize this structure, shifting the equilibrium toward the folded state and reducing the production of the oncogenic protein (Xodo et al., 2016, Quarterly Reviews of Biophysics). This approach is particularly valuable for targeting KRAS variants that remain difficult to inhibit with traditional protein-directed small molecules.

Other names

KRAS 5'-UTR G-quadruplexKRAS G4KRAS messenger RNA G-quadruplexKRAS G-rich sequence

Stabilization of the G-quadruplex structure within the 5'-untranslated region (5'-UTR) of KRAS mRNA to sterically hinder the translation machinery and inhibit protein synthesis.