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

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作者
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
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[1] Regeneron Pharmaceuticals,
[2] Inc.,undefined
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Nature Communications | / 14卷
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摘要
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.
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