8RJ5

P1-15 T-cell Receptor bound to HLA A*2402-NF9 pMHC complex

Summary for 8RJ5

• Entry DOI: 10.2210/pdb8rj5/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, Spike protein S1, ... (5 entities in total)
• Functional Keywords: t-cell receptor, peptide:hla, nf9, covid-19, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 190869.91

Authors

Wall, A.,Sewell, A.K.,Motozono, C.,Rizkallah, P.J.,Fuller, A. (deposition date: 2023-12-20, release date: 2025-01-01, Last modification date: 2026-07-15)

Primary citation

Nakama, T.,Wall, A.,Dolton, G.,Tan, L.R.,Thomas, H.,Hamana, H.,Aritsu, Y.,Tan, T.S.,Toyoda, M.,Goto, Y.,Li, H.,Kitamatsu, M.,Udaka, K.,Miyashita, Y.,Oshiumi, H.,Nakamura, K.,Nagasaki, Y.,Minami, R.,Nakata, H.,Rizkallah, P.J.,Kishi, H.,Ueno, T.,Sewell, A.K.,Motozono, C.
Position-5-driven reorientation of an immunodominant HLA-A*24:02 SARS-CoV-2 epitope drives universal T cell escape.
JCI Insight, 11:-, 2026

PubMed Abstract: Cytotoxic T lymphocytes form a critical component of SARS-CoV-2 immunity by recognizing viral peptides bound to HLA class I molecules. Here, we identified the spike-derived peptide NYNYLYRLF448-456 (NF9) as the immunodominant HLA-A*24:02-restricted epitope in both convalescent and vaccinated donors. Across cohorts, A24/NF9-specific responses were dominated by public TCR motifs featuring TRAV12-1 paired with TRBJ2-7 and a conserved CDR3β sequence (CASSXXXGYEQYF). Using a panel of 13 TCRs, we mapped recognition of single amino acid substitutions within NF9 and identified residue 5 (L452) as the principal determinant of escape. The L452R substitution, characteristic of the Delta variant, abolished recognition across all tested TCRs despite preserved HLA binding. Crystallography of a representative public TCR (P1-15) revealed that mutation at position-5 reoriented the peptide within HLA-A*24:02, flipping the adjacent Y453 side chain into the peptide-binding groove and eliminating the dominant TCR contact. This position-5-driven conformational switch provided a structural mechanism for universal loss of NF9 recognition by HLA-A*24:02-restricted T cells. Consistent with this, Delta-infected convalescents failed to mount de novo NF9-5R-specific responses while retaining responses to the conserved A24/QI9 spike epitope. Together, these findings defined the basis of A24/NF9 recognition and showed how 1 mutation remodeled peptide presentation to abrogate TCR responses.

PubMed: 41842944
DOI: 10.1172/jci.insight.202235

Experimental method

X-RAY DIFFRACTION (3.02 Å)