Unraveling atomic-scale mechanisms of GDP extraction catalyzed by SOS1 in KRAS-G12 and KRAS-D12 oncogenes.

The guanine exchange factor SOS1 plays a pivotal role in the positive feedback regulation of the KRAS signaling pathway. Recently, the regulation of KRAS-SOS1 interactions and KRAS downstream effector proteins has emerged as a key focus in the development of therapies targeting KRAS-driven cancers. However, the detailed dynamic mechanisms underlying SOS1-catalyzed GDP extraction and the impact of KRAS mutations remain largely unexplored. In this study, we unveil and describe in atomic detail the primary mechanisms by which SOS1 facilitates GDP extraction from KRAS oncogenes. For GDP-bound wild-type KRAS (KRAS-G12), four critical amino acids (Lys811, Glu812, Lys939, and Glu942) are identified as essential for the catalytic function of SOS1. Notably, the KRAS-G12D mutation (KRAS-D12) significantly accelerates the rate of GDP extraction. The molecular basis of this enhancement are attributed to hydrogen bonding interactions between the mutant residue Asp12 and a positively charged pocket in the intrinsically disordered region (residues 807-818), comprising Ser807, Trp809, Thr810, and Lys811. These findings provide novel insights into SOS1-KRAS interactions and offer a foundation for developing anti-cancer strategies aimed at disrupting these mechanisms.