8WUL

Crystal structure of affinity enhanced TCR in complex with HLA-A*11:01 bound to KRAS-G12V peptide (VVGAVGVGK)

Summary for 8WUL

• Entry DOI: 10.2210/pdb8wul/pdb
• Descriptor: TCR alpha chain, TCR beta chain, MHC class I antigen, ... (6 entities in total)
• Functional Keywords: t cell receptor, kras-g12v, hla-a*11:01, immune system
• Biological source: Mus musculus; More
• Total number of polymer chains: 20
• Total formula weight: 374749.94

Authors

Zhang, M.Y.,Luo, L.J.,Xu, W.,Guan, F.H.,Wang, X.Y.,Zhu, P.,Zhang, J.H.,Zhou, X.Y.,Wang, F.,Ye, S. (deposition date: 2023-10-20, release date: 2024-05-01, Last modification date: 2024-10-16)

Primary citation

Zhang, M.,Xu, W.,Luo, L.,Guan, F.,Wang, X.,Zhu, P.,Zhang, J.,Zhou, X.,Wang, F.,Ye, S.
Identification and affinity enhancement of T-cell receptor targeting a KRAS G12V cancer neoantigen.
Commun Biol, 7:512-512, 2024

PubMed Abstract: Neoantigens derived from somatic mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), the most frequently mutated oncogene, represent promising targets for cancer immunotherapy. Recent research highlights the potential role of human leukocyte antigen (HLA) allele A*11:01 in presenting these altered KRAS variants to the immune system. In this study, we successfully generate and identify murine T-cell receptors (TCRs) that specifically recognize KRAS from three predicted high affinity peptides. By determining the structure of the tumor-specific 4TCR2 bound to KRAS-HLA-A*11:01, we conduct structure-based design to create and evaluate TCR variants with markedly enhanced affinity, up to 15.8-fold. This high-affinity TCR mutant, which involved only two amino acid substitutions, display minimal conformational alterations while maintaining a high degree of specificity for the KRAS peptide. Our research unveils the molecular mechanisms governing TCR recognition towards KRAS neoantigen and yields a range of affinity-enhanced TCR mutants with significant potential for immunotherapy strategies targeting tumors harboring the KRAS mutation.

PubMed: 38684865
DOI: 10.1038/s42003-024-06209-2

Experimental method

X-RAY DIFFRACTION (2.36 Å)