9LLU

p53 epitope specific TCR 4414A binding to p53Y220D-HLA-A2

Summary for 9LLU

• Entry DOI: 10.2210/pdb9llu/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, VAL-VAL-PRO-ASP-GLU-PRO-PRO-GLU-VAL, ... (5 entities in total)
• Functional Keywords: p53, neoantigen, tcr, hla-a2, immunesystem, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 95825.21

Authors

Duan, Z.H.,Wu, D.C. (deposition date: 2025-01-17, release date: 2026-07-22, Last modification date: 2026-09-23)

Primary citation

Duan, Z.,Zhao, J.,Wu, J.,Zhang, Y.,Yuan, P.,Zeng, Y.,Jin, H.,Mariuzza, R.A.,Wu, D.
Structural basis for T-cell receptor recognition of p53 Y220D , a human cancer neoantigen.
Acta Crystallogr D Struct Biol, 82:1082-1092, 2026

PubMed Abstract: Adoptive cell therapy (ACT) with tumor-specific T cells can mediate durable cancer regression. The main target of tumor-specific T cells are neoantigens resulting from mutations in self-antigens over the course of malignant transformation. To understand T-cell recognition of cancer neoantigens at the atomic level, we studied a T-cell receptor (TCR 4414A) that recognizes a neoepitope arising from a driver mutation in the p53 oncogene (p53) presented by HLA-A2. Here, we report the structure of TCR 4414A bound to HLA-A2 and p53, as well as structures of unbound wild-type and mutant p53-HLA-A2 ligands. The structures reveal that the Y220D mutation induces a conformational change in the p53 neoepitope that is detected by TCR 4414A, thereby rendering a normally cryptic self-peptide visible to T cells. The TCR minimizes interactions with the N- and C-terminal portions of p53, which are identical in mutant and wild-type peptides, and instead focuses on the Y220D driver mutation at the peptide center. In this way, TCR 4414A achieves highly specific recognition of mutant over wild-type p53, a critical parameter for avoiding off-target toxicities in ACT.

PubMed: 42599692
DOI: 10.1107/S2059798326007564

Experimental method

X-RAY DIFFRACTION (2.87 Å)