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

By 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

Posted 19 Aug 2022
bioRxiv DOI: 10.1101/2022.08.18.504455

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 a/b 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.

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