9PBH

AS19.2 TCR complex with PSG5-HLA B*27:05

Summary for 9PBH

• Entry DOI: 10.2210/pdb9pbh/pdb
• Related: 9PBG
• Descriptor: MHC class I antigen, Beta-2-microglobulin, Pregnancy-specific beta-1-glycoprotein 5, ... (8 entities in total)
• Functional Keywords: tcr, complex, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 95962.17

Authors

Jude, K.M.,Wang, N.,Garcia, K.C. (deposition date: 2025-06-26, release date: 2026-03-18, Last modification date: 2026-06-10)

Primary citation

Wang, N.,Yeh, H.,Lai, B.,Perera, J.,Jude, K.M.,Risch, I.,Um, J.,Chen, X.,Xiang, X.,Wang, C.,Liu, L.D.,Yang, X.,Paley, M.A.,Khan, A.A.,Garcia, K.C.
Deep peptide recognition profiling decodes TCR specificity and enables disease-associated antigen discovery.
Nat.Biotechnol., 2026

PubMed Abstract: Predicting T cell receptor (TCR) specificity on the basis of sequence is challenging because TCRs of similar sequence can recognize entirely different antigens, whereas TCRs of different sequence can recognize the same antigens. Here we present a system that integrates high-throughput yeast display with fine-tuned protein language models (pLMs) to generate deep peptide recognition profiles (PRPs) for individual TCRs, each detailing binding against millions of peptides. We provide detailed PRPs for a panel of HLA-B*27:05-restricted TCRs from persons with ankylosing spondylitis and acute anterior uveitis that almost exclusively recognize peptides through CDR3β. pLMs trained on these PRPs outperform AlphaFold3 and tFold-TCR in predicting T cell activation. We discover and validate novel candidate autoantigens, demonstrate that model generalization to new TCRs correlates with functional distance (PRP divergence) rather than sequence similarity and introduce a model-intrinsic uncertainty metric to quantify prediction confidence. This system and its associated PRP datasets offer a scalable approach to mapping TCR recognition, accelerating antigen discovery and guiding TCR engineering.

PubMed: 42129507
DOI: 10.1038/s41587-026-03128-x

Experimental method

X-RAY DIFFRACTION (2.13 Å)