Human Cancer Target-Medicilon's KRAS-targeted Drugs R&D Service: Structure of KRAS

RAS is one of the most frequently mutated oncogenes in human cancer. KRAS is the isoform most frequently mutated, which constitutes about 85% of RAS mutations. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. KRAS protein contains four domains. KRAS protein is made up of six beta-strands (forming the protein core) and five alpha-helices, which form two major domains: G-domain and C-terminal. The G domain of KRAS, comprised of residues 1-166, includes the GTP-binding pocket, a region within which is essential for the interactions between the putative downstream effectors and GTPase-activating proteins. The G domain is highly conserved and contains switch I and switch II loops, which are responsible for GDP-GTP exchange. The C-terminal, a hypervariable region including the CAAX (C=cysteine, A=any aliphatic amino acid, X=any amino acid) motif, guides posttranslational modifications and determines plasma membrane anchoring. This region plays an important role in the regulation of the biological activity of RAS protein.