Structure guided analysis of KRAS G12 mutants in HLA-A*11:01 reveals a length encoded immunogenic advantage in G12D.

ABSTRACT: KRAS G12 mutations are frequent oncogenic drivers, yet their differential immunogenicity complicates T cell-based therapies. Here, we integrate structural, biophysical, and functional analyses to examine how KRAS G12 variants remodel peptide-MHC-I (pMHC) architecture and T cell receptor (TCR) recognition. Using HLA-A*11:01, we show that single residue substitutions at position 12 induce distinct conformational changes in the MHC groove, with G12D uniquely destabilizing the complex through a buried aspartate side chain. Notably, G12D peptides adopt two registers, a 9-mer and a 10-mer, that diverge sharply in structure and immunogenicity. The 10-mer forms a compact, stable pMHC with a TCR-accessible surface, while the 9-mer adopts a bent conformation incompatible with recognition. Molecular

SUBMITTER: Zhu J 

PROVIDER: S-EPMC12774912 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature