6L9N
H2-Ld complexed with A5 peptide
Summary for 6L9N
| Entry DOI | 10.2210/pdb6l9n/pdb |
| Descriptor | MHC, b2m, SER-PRO-SER-TYR-ALA-TYR-HIS-GLN-PHE, ... (4 entities in total) |
| Functional Keywords | major histocompatibility complex, immune system |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 12 |
| Total formula weight | 179725.08 |
| Authors | |
| Primary citation | Wei, P.,Jordan, K.R.,Buhrman, J.D.,Lei, J.,Deng, H.,Marrack, P.,Dai, S.,Kappler, J.W.,Slansky, J.E.,Yin, L. Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer. Proc.Natl.Acad.Sci.USA, 118:-, 2021 Cited by PubMed Abstract: Tumors frequently express unmutated self-tumor-associated antigens (self-TAAs). However, trial results using self-TAAs as vaccine targets against cancer are mixed, often attributed to deletion of T cells with high-affinity receptors (TCRs) for self-TAAs during T cell development. Mutating these weak self-TAAs to produce higher affinity, effective vaccines is challenging, since the mutations may not benefit all members of the broad self-TAA-specific T cell repertoire. We previously identified a common weak murine self-TAA that we converted to a highly effective antitumor vaccine by a single amino acid substitution. In this case the modified and natural self-TAAs still raised very similar sets of CD8 T cells. Our structural studies herein show that the modification of the self-TAA resulted in a subtle change in the major histocompatibility complex I-TAA structure. This amino acid substitution allowed a dramatic conformational change in the peptide during subsequent TCR engagement, creating a large increase in TCR affinity and accounting for the efficacy of the modified self-TAA as a vaccine. These results show that carefully selected, well-characterized modifications to a poorly immunogenic self-TAA can rescue the immune response of the large repertoire of weakly responding natural self-TAA-specific CD8 T cells, driving them to proliferate and differentiate into functional effectors. Subsequently, the unmodified self-TAA on the tumor cells, while unable to drive this response, is nevertheless a sufficient target for the CD8 cytotoxic effectors. Our results suggest a pathway for more efficiently identifying variants of common self-TAAs, which could be useful in vaccine development, complementing other current nonantigen-specific immunotherapies. PubMed: 34074778DOI: 10.1073/pnas.2100588118 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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