21EX

Wild tipe p53WT-HLA-A2

Summary for 21EX

• Entry DOI: 10.2210/pdb21ex/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, Cellular tumor antigen p53, ... (4 entities in total)
• Functional Keywords: wild tipe, p53wt, hla-a2, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 44889.84

Authors

Duan, Z.H.,Wu, D.C. (deposition date: 2025-12-10, release date: 2026-09-09)

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, 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 (2.021 Å)