9J4T

Structural basis for recognition of SARS-CoV-2 conserved nucleocapside epitopes by dominant T cell receptors

Summary for 9J4T

• Entry DOI: 10.2210/pdb9j4t/pdb
• Descriptor: HLA class I histocompatibility antigen, B alpha chain, Beta-2-microglobulin, Nucleoprotein, ... (6 entities in total)
• Functional Keywords: tcr, t cell receptor, sars-cov-2, nucleocapside, hla-b7, viral protein/immune system, viral protein-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 95622.05

Authors

Yuan, P.,Wu, D.C. (deposition date: 2024-08-10, release date: 2025-08-13, Last modification date: 2026-01-07)

Primary citation

Yuan, P.,Chen, G.,Li, Y.,Liu, X.,Saravanakumar, S.,Zhao, J.,Ji, Q.,Wang, H.,Lin, Y.W.,Elbahnasawy, M.,Weng, N.P.,Pierce, B.G.,Mariuzza, R.A.,Wu, D.
Structural insights into clonal restriction and diversity in T cell recognition of two immunodominant SARS-CoV-2 nucleocapsid epitopes.
Nat Commun, 16:11457-11457, 2025

PubMed Abstract: T cells play a crucial role in clearing SARS-CoV-2 and in forming long-term memory responses to that coronavirus. The highly immunogenic nucleocapsid (N) protein of SARS-CoV-2 is much more conserved than the spike (S) protein across variants of concern, making it an attractive vaccine target for activating cytotoxic CD8 T cells. Of particular interest are the immunodominant N epitopes LLL and SPR. Whereas LLL elicits a clonally restricted T cell response, the response to SPR is highly diverse. To understand the basis for this difference, here we determine structures of T cell receptors (TCRs) bound to LLL-HLA-A2 and SPR-HLA-B7, revealing the structural underpinnings of highly restricted Vα gene usage by LLL-specific TCRs, as well as multiple structural solutions to recognizing SPR and thereby generating a clonally diverse T cell response to that epitope. These structures also provide frameworks for understanding T cell recognition of SARS-CoV-2 variants and other coronaviruses. Finally, we compare the X-ray structures of TCR-LLL-HLA-A2 and TCR-SPR-HLA-B7 complexes with models predicted by multiple versions of AlphaFold, highlighting some success while showing room for improvement. Overall, our findings expand understanding of coronavirus T cell recognition, informing vaccine design and advances in computational modeling approaches.

PubMed: 41372155
DOI: 10.1038/s41467-025-66322-6

Experimental method

X-RAY DIFFRACTION (2.04 Å)