Structural characterization and AlphaFold modeling of human T cell receptor recognition of NRAS cancer neoantigens @ScienceAdvances • This study reveals crystal structures of the human T cell receptor (TCR) N17.1.2 in complex with NRAS Q61K and Q61R neoantigen peptides bound to HLA-A1, uncovering the structural basis for mutant-specific recognition critical for immunotherapy. • TCR N17.1.2 demonstrates exquisite specificity for mutant NRAS neoantigens, discriminating effectively against wild-type NRAS peptides through direct targeting of the P7 Lys/Arg mutation, a key determinant for immune recognition. • Surface plasmon resonance assays confirm high-affinity binding (1.2 μM for Q61K and 3.4 μM for Q61R) of the TCR to the mutant neoantigens, while no binding is observed with wild-type peptides. • The study highlights the dominant role of the TCR Vα domain in MHC interactions and the Vβ domain in peptide recognition, particularly through the CDR3β loop forming critical salt bridges with the mutant residues. • AlphaFold2 and AlphaFold3 models accurately predicted the TCR-peptide-MHC complexes when enhanced sampling methods (e.g., 1000-model generation) were applied, showcasing the potential and limitations of AI-driven structural prediction for immune complexes. • This work advances the understanding of TCR neoantigen recognition, providing a structural framework to design optimized TCRs for adoptive cell therapy targeting NRAS mutations in aggressive cancers like melanoma. 📜Paper: science.org/doi/10.1126/scia… #Immunotherapy #CancerNeoantigens #AlphaFold #StructuralBiology #TCellReceptors #Bioinformatics #OpenScience