3QDJ

The complex between TCR DMF5 and human Class I MHC HLA-A2 with the bound MART-1(27-35) nonameric peptide

Summary for 3QDJ

• Entry DOI: 10.2210/pdb3qdj/pdb
• Related: 3QDG 3QDM 3QEQ 3QEU
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, MART-1(27-35) peptide, ... (6 entities in total)
• Functional Keywords: mart-1 peptide, nonapeptide, mhc class i, hla-a2, tcr dmf5, tcr dmf4, cross-reactivity, cancer, melanoma, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted: P61769
• Total number of polymer chains: 5
• Total formula weight: 93482.76

Authors

Borbulevych, O.Y.,Baker, B.M. (deposition date: 2011-01-18, release date: 2011-07-06, Last modification date: 2023-09-13)

Primary citation

Borbulevych, O.Y.,Santhanagopolan, S.M.,Hossain, M.,Baker, B.M.
TCRs Used in Cancer Gene Therapy Cross-React with MART-1/Melan-A Tumor Antigens via Distinct Mechanisms.
J.Immunol., 187:2453-2463, 2011

PubMed Abstract: T cells engineered to express TCRs specific for tumor Ags can drive cancer regression. The first TCRs used in cancer gene therapy, DMF4 and DMF5, recognize two structurally distinct peptide epitopes of the melanoma-associated MART-1/Melan-A protein, both presented by the class I MHC protein HLA-A*0201. To help understand the mechanisms of TCR cross-reactivity and provide a foundation for the further development of immunotherapy, we determined the crystallographic structures of DMF4 and DMF5 in complex with both of the MART-1/Melan-A epitopes. The two TCRs use different mechanisms to accommodate the two ligands. Although DMF4 binds the two with a different orientation, altering its position over the peptide/MHC, DMF5 binds them both identically. The simpler mode of cross-reactivity by DMF5 is associated with higher affinity toward both ligands, consistent with the superior functional avidity of DMF5. More generally, the observation of two diverging mechanisms of cross-reactivity with the same Ags and the finding that TCR-binding orientation can be determined by peptide alone extend our understanding of the mechanisms underlying TCR cross-reactivity.

PubMed: 21795600
DOI: 10.4049/jimmunol.1101268

Experimental method

X-RAY DIFFRACTION (2.3 Å)