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TitleStructural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 2401, Year 2023
Publish dateApr 26, 2023
AuthorsKei 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 /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:37100770 / PubMed Central
MethodsEM (single particle)
Resolution2.65 - 3.4 Å
Structure data

EMDB-28570, PDB-8es7:
CryoEM structure of PN45545 TCR-CD3 complex
Method: EM (single particle) / Resolution: 3.04 Å

EMDB-28571, PDB-8es8:
CryoEM structure of PN45545 TCR-CD3 in complex with HLA-A2 MAGEA4 (230-239)
Method: EM (single particle) / Resolution: 2.65 Å

EMDB-28572, PDB-8es9:
CryoEM structure of PN45428 TCR-CD3 in complex with HLA-A2 MAGEA4
Method: EM (single particle) / Resolution: 3.25 Å

EMDB-28573, PDB-8esa:
CryoEM structure of HLA-A2 bound to MAGEA4 (230-239) peptide
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-28574, PDB-8esb:
CryoEM structure of HLA-A2 bound to MAGEA8 (232-241) peptide
Method: EM (single particle) / Resolution: 3.12 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / TCR / membrane protein / CD3 / HLA / MHC / receptor

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