9ZET

TCR AS4.2 bound to single-chain PRPF3-B2M-HLA-B*27:05

Summary for 9ZET

• Entry DOI: 10.2210/pdb9zet/pdb
• EMDB information: 74119
• Descriptor: single-chain PRPF3-B2M-HLA-B*27:05, T cell receptor alpha chain, T cell receptor beta chain (3 entities in total)
• Functional Keywords: tcr, pmhc, germline, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 126142.00

Authors

Wang, N.,Borowska, M.T.,Jude, K.M.,Garcia, K.C. (deposition date: 2025-11-30, release date: 2026-11-04)

Primary citation

Wang, N.,Borowska, M.T.,Jude, K.M.,Chen, X.,Wang, C.,Xiang, X.,Liu, L.D.,Ma, R.,Motiani, A.,Wilson, S.C.,Liu, W.,Garcia, K.C.
MHC restriction is structurally encoded by the T cell receptor germline.
Biorxiv, 2026

PubMed Abstract: MHC restriction - the requirement for αβ T cell receptors (TCRs) to recognize Major Histocompatibility Complex (MHC) molecules when presenting peptide antigens - is a pillar of adaptive immunity. Here, we provide direct structural evidence for TCR germline-encoded recognition of MHC molecules irrespective of antigenic peptide. We engineered "germline-like" TCRs to eliminate CDR3 specificity for peptide, and a molecular clamping strategy to trap ultra-low-affinity complexes with peptide-MHC for cryo-EM. We find that germline-like TCR/pMHC docking modes are identical to wild-type T cell receptors with intact CDR3 loops, across distinct peptide antigens and MHC alleles. Analysis of human TCR repertoires reveals enrichment of specific V genes and Vα-Vβ pairing patterns associated with HLA-A*02 contexts. Thus, the TCR germline encodes the blueprint for MHC restriction, providing a sequence-based framework that could inform computational and AI-driven prediction of TCR specificity.

PubMed: 42856299
DOI: 10.64898/2026.09.24.754241

Experimental method

ELECTRON MICROSCOPY (2.8 Å)