Nature Communications (Apr 2023)

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

  • 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. Franklin

DOI
https://doi.org/10.1038/s41467-023-37532-7
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 12

Abstract

Read online

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.