Hu, Z.; Marti, J.

The guanine exchange factor SOS1 is a crucial node into the positive feedback regulation of the KRAS signaling pathway. Currently, the regulation of KRAS-SOS1 interactions and KRAS downstream effector proteins has become a new hotspot in the development of KRAS-driven cancer therapies. However, the detailed dynamic mechanisms of SOS1-catalyzed GDP extraction and the impact of KRAS mutations remain unknown. Herein, the main mechanisms of GDP extraction from KRAS oncogenes by means of the guanine exchange factor SOS1 are disclosed and described with full details at the atomic-level. For GDP-bound wild-type KRAS, four amino acids (Lys811, Glu812, Lys939 and Glu942) responsible for the catalytic function of SOS1 were identified. With the occurrence of KRAS-G12D mutation, the GDP extraction rate is significantly increased. The molecular interactions behind this phenomenon have been subsequently identified being mainly hydrogen bonding interactions between the mutated residue Asp12 and a positively charged pocket located at the intrinsically disordered region807-818 and composed by Ser807, Trp809, Thr810 and Lys811. Our findings provide new insights into the SOS1-KRAS interactions and facilitate the development of related anti-cancer strategies based on the blockage of the above described mechanisms.