Structural insights of the complex formed by KRAS G12V and a novel TIG3 peptide

Abstract

Pancreatic cancer remains a severe malignancy with a dismal 5-year survival rate, and most pancreatic cancer patients harbor KRAS mutations, which are critical targets for anti-cancer drug development. However, the structural characteristics of KRAS present challenges for therapeutic targeting. In this study, we developed a novel peptide derived from TIG3 protein, a type II tumor suppressor, and confirmed its moderate affinity binding to KRAS G12V. X-ray crystallography revealed that this peptide binds near the Switch II domain of KRAS G12V, causing conformational changes likely to affect its activity. Furthermore, the peptide reduced the viability of cancer cell lines harboring the KRAS G12V mutation, thus demonstrating its potential as a KRAS G12V inhibitor. Our results indicate that the developed novel TIG3 peptide is a promising candidate for KRAS-targeted therapy and provide structural insights useful for the development of pancreatic ductal adenocarcinoma therapeutics.