Xiaojing Chen
Postdoctoral Scholar, Molecular and Cellular Physiology
All Publications
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Solution mapping of MHC-I:TCR interactions using a minimalistic protein system.
Proceedings of the National Academy of Sciences of the United States of America
2025; 122 (24): e2506016122
Abstract
Recognition of epitopic peptide antigens presented on class I major histocompatibility complex (MHC-I) proteins by T cell receptors (TCRs) forms the cornerstone of immune surveillance, leading to a plethora of adaptive immune responses. Characterization of TCR:peptide/MHC-I interactions is critical for understanding immune recognition, and developing immunotherapies, but the large variation in docking orientations of TCRs on their peptide/MHC-I targets challenges structural modeling. NMR spectroscopy could potentially resolve this ambiguity, but the large size of the TCR:peptide/MHC-I complex limits data quality. Here, we demonstrate that a designed MHC-I protein, SMART A*02:01, enables facile solution mapping of MHC-I:TCR interactions at scale. Our approach can be combined with computational modeling and structure-guided engineering to aid the development of TCR-based therapeutics.
View details for DOI 10.1073/pnas.2506016122
View details for PubMedID 40489613
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De novo design and structure of a peptide-centric TCR mimic binding module.
bioRxiv : the preprint server for biology
2024
Abstract
T cell receptor (TCR) mimics offer a promising platform for tumor-specific targeting of peptide-MHC in cancer immunotherapy. Here, we designed a de novo α-helical TCR mimic (TCRm) specific for the NY-ESO-1 peptide presented by HLA-A*02, achieving high on-target specificity with nanomolar affinity (Kd = 9.5 nM). The structure of the TCRm/pMHC complex at 2.05 Å resolution revealed a rigid TCR-like docking mode with an unusual degree of focus on the up-facing NY-ESO-1 side chains, suggesting the potential for reduced off-target reactivity. Indeed, a structure-informed in silico screen of 14,363 HLA-A*02 peptides correctly predicted two off-target peptides, yet our TCRm maintained a wide therapeutic window as a T cell engager. These results represent a path for precision targeting of tumor antigens with peptide-focused α-helical TCR mimics.
View details for DOI 10.1101/2024.12.16.628822
View details for PubMedID 39763827
View details for PubMedCentralID PMC11702606