8WTE

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

8WTE の概要

• エントリーDOI: 10.2210/pdb8wte/pdb
• 分子名称: T-cell receptor alpha chain, T-cell receptor beta chain, MHC class I antigen (Fragment), ... (6 entities in total)
• 機能のキーワード: t cell receptor, kras-g12v, hla-a*11:01, immune system
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 187611.10

構造登録者

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. (登録日: 2023-10-18, 公開日: 2024-05-01, 最終更新日: 2024-10-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.17 Å)