6L9M

H2-Ld complexed with AH1 peptide

6L9M の概要

• エントリーDOI: 10.2210/pdb6l9m/pdb
• 分子名称: H2-Ld, b2m, SER-PRO-SER-TYR-VAL-TYR-HIS-GLN-PHE, ... (4 entities in total)
• 機能のキーワード: major histocompatibility complex, immune system
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 179837.29

構造登録者

Wei, P.C.,Yin, L. (登録日: 2019-11-10, 公開日: 2020-11-18, 最終更新日: 2024-11-13)

主引用文献

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

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: 34074778
DOI: 10.1073/pnas.2100588118

実験手法

X-RAY DIFFRACTION (2.6 Å)