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

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 dynamics and NMR titration confirm the superior stability and binding affinity of the 10-mer. These results highlight how peptide length and conformation critically shape immune visibility, offering mechanistic insight for optimizing TCR-T therapies against elusive neoantigens like KRAS G12D.

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Journal
Communications Biology
Published
2025-12-03
DOI
https://doi.org/10.1038/s42003-025-09285-0
Primary Topic
T-cell and B-cell Immunology
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Hongjuan Xue, Shuqing Wang, Hongwei Jin, Xi Xu et al.
Communications Biology
T-cell and B-cell Immunology
article

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

Hongjuan Xue, Shuqing Wang, Hongwei Jin, Xi Xu, Maorong Wen, Jiali Zhu, Quanmeng Wang, Zhifeng Chen, Linlin Zhao, Yuxuan Wang, Pei Liu, Yuchen He, Ke Xu
article en

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 dynamics and NMR titration confirm the superior stability and binding affinity of the 10-mer. These results highlight how peptide length and conformation critically shape immune visibility, offering mechanistic insight for optimizing TCR-T therapies against elusive neoantigens like KRAS G12D.

Communications BiologyVol. 9(1)
Tongji University (CN), Chinese Academy of Sciences (CN), Peking University (CN), Shanghai Advanced Research Institute (CN), Shanghai Tenth People's Hospital (CN), Central Hospital of Putuo District (CN), Hangzhou DAC Biotech (China) (CN), Tongji Hospital (CN), Shanghai Center for Brain Science and Brain-Inspired Technology (CN), Tianjin Medical University (CN)
Salt Science Research Foundation, National Natural Science Foundation of China
Openalex Percentile: Top 57%
T-cell and B-cell Immunology
DOIOpen Access PDFOpenAlex
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