9UV8

Crystal structure of HLA-A*11:01 in complex with KRAS G12D 9-mer peptide (VVGADGVGK)

Summary for 9UV8

• Entry DOI: 10.2210/pdb9uv8/pdb
• Descriptor: HLA class I histocompatibility antigen, A alpha chain, Beta-2-microglobulin, KRAS G12D-9mer (VVGADGVGK), ... (4 entities in total)
• Functional Keywords: complex, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 46953.93

Authors

Jiali, Z.,Linlin, Z. (deposition date: 2025-05-09, release date: 2025-12-24, Last modification date: 2026-01-21)

Primary citation

Zhu, J.,Chen, Z.,Xu, X.,Wang, Y.,Liu, P.,Wen, M.,Wang, Q.,He, Y.,Jin, H.,Xue, H.,Wang, S.,Xu, K.,Zhao, L.
Structure guided analysis of KRAS G12 mutants in HLA-A*11:01 reveals a length encoded immunogenic advantage in G12D.
Commun Biol, 9:26-26, 2025

PubMed 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.

PubMed: 41339521
DOI: 10.1038/s42003-025-09285-0

Experimental method

X-RAY DIFFRACTION (1.79 Å)