9WK0

Neoantigen Rac1P29S-HLA-A2

Summary for 9WK0

• Entry DOI: 10.2210/pdb9wk0/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, PHE-SER-GLY-GLU-TYR-ILE-PRO-THR-VAL, ... (4 entities in total)
• Functional Keywords: neoantigen, rac1p29s, hla-a2, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 44876.87

Authors

Yang, D.D.,Wu, D.C. (deposition date: 2025-08-31, release date: 2026-06-17)

Primary citation

Zeng, Y.,Yang, D.,Zhao, J.,Yuan, P.,Jin, H.,Liao, W.,Chen, G.,Wu, D.
Structural basis for TCR recognition of a Rac1 neoantigen arising from anchor residue mutation.
J.Struct.Biol., 218:108329-108329, 2026

PubMed Abstract: T cell receptor (TCR)-based immunotherapy can drive cancer regression by targeting neoantigens derived from mutations in self-proteins. Most neoantigens result from mutations in solvent-exposed residues creating neoepitopes that allow highly specific TCR recognition. Here, we describe a melanoma neoantigen (Rac1) caused by a mutation at a primary anchor residue. Unlike typical cases, the immunogenicity of Rac1 stems from this anchor mutation, which permits MHC presentation of the mutant peptide but not the wild-type counterpart. We determined the structures of both the mutant Rac1-HLA-A2 complex and its complex with the tumor-specific TCR 5934. These structures show how the P29S mutation makes a Rac1 self- peptide visible to T cells. Notably, TCR 5934 primarily engages the C-terminal, non-mutated P8 threonine residue of Rac1 -far from the N-terminal mutated P2 serine. This contrasts with most neoantigen-specific TCRs, which typically focus on the mutated residue to distinguish mutant from wild-type peptides. Together, these findings provide a structural framework to guide the development of TCR-based cancer immunotherapies.

PubMed: 42190883
DOI: 10.1016/j.jsb.2026.108329

Experimental method

X-RAY DIFFRACTION (1.8 Å)