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All Publications

  • 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 Woodward, C. H., Chaudhuri, A., Chen, X. T., White, W. L., Garcia, K. C., Baker, D., Sgourakis, N. G. 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

  • De novo design and structure of a peptide-centric TCR mimic binding module. bioRxiv : the preprint server for biology Householder, K. D., Xiang, X., Jude, K. M., Deng, A., Obenaus, M., Wilson, S. C., Chen, X., Wang, N., Garcia, K. C. 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