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Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM

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Listed:
  • Kei Saotome

    (Regeneron Pharmaceuticals, Inc.)

  • Drew Dudgeon

    (Regeneron Pharmaceuticals, Inc.)

  • Kiersten Colotti

    (Regeneron Pharmaceuticals, Inc.)

  • Michael J. Moore

    (Regeneron Pharmaceuticals, Inc.)

  • Jennifer Jones

    (Regeneron Pharmaceuticals, Inc.)

  • Yi Zhou

    (Regeneron Pharmaceuticals, Inc.)

  • Ashique Rafique

    (Regeneron Pharmaceuticals, Inc.)

  • George D. Yancopoulos

    (Regeneron Pharmaceuticals, Inc.)

  • Andrew J. Murphy

    (Regeneron Pharmaceuticals, Inc.)

  • John C. Lin

    (Regeneron Pharmaceuticals, Inc.)

  • William C. Olson

    (Regeneron Pharmaceuticals, Inc.)

  • Matthew C. Franklin

    (Regeneron Pharmaceuticals, Inc.)

Abstract

The recognition of antigenic peptide-MHC (pMHC) molecules by T-cell receptors (TCR) initiates the T-cell mediated immune response. Structural characterization is key for understanding the specificity of TCR-pMHC interactions and informing the development of therapeutics. Despite the rapid rise of single particle cryoelectron microscopy (cryoEM), x-ray crystallography has remained the preferred method for structure determination of TCR-pMHC complexes. Here, we report cryoEM structures of two distinct full-length α/β TCR-CD3 complexes bound to their pMHC ligand, the cancer-testis antigen HLA-A2/MAGEA4 (230–239). We also determined cryoEM structures of pMHCs containing MAGEA4 (230–239) peptide and the closely related MAGEA8 (232–241) peptide in the absence of TCR, which provided a structural explanation for the MAGEA4 preference displayed by the TCRs. These findings provide insights into the TCR recognition of a clinically relevant cancer antigen and demonstrate the utility of cryoEM for high-resolution structural analysis of TCR-pMHC interactions.

Suggested Citation

  • Kei Saotome & Drew Dudgeon & Kiersten Colotti & Michael J. Moore & Jennifer Jones & Yi Zhou & Ashique Rafique & George D. Yancopoulos & Andrew J. Murphy & John C. Lin & William C. Olson & Matthew C. F, 2023. "Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37532-7
    DOI: 10.1038/s41467-023-37532-7
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    References listed on IDEAS

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    1. De Dong & Lvqin Zheng & Jianquan Lin & Bailing Zhang & Yuwei Zhu & Ningning Li & Shuangyu Xie & Yuhang Wang & Ning Gao & Zhiwei Huang, 2019. "Structural basis of assembly of the human T cell receptor–CD3 complex," Nature, Nature, vol. 573(7775), pages 546-552, September.
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