6TRO

Crystal structure of the T-cell receptor GVY01 bound to HLA A2*01-GVYDGREHTV

6TRO の概要

• エントリーDOI: 10.2210/pdb6tro/pdb
• 関連するPDBエントリー: 6TRN
• 分子名称: MHC class I antigen, Beta-2-microglobulin, MAGE-A4 peptide (amino acids 230-239), ... (6 entities in total)
• 機能のキーワード: human leukocyte antigen, mage-a4, t-cell receptor, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 96383.17

構造登録者

Coles, C.H.,McMurran, C.,Lloyd, A.,Hibbert, L.,Lupardus, P.J.,Cole, D.K.,Harper, S. (登録日: 2019-12-19, 公開日: 2020-06-24, 最終更新日: 2024-10-23)

主引用文献

Coles, C.H.,McMurran, C.,Lloyd, A.,Hock, M.,Hibbert, L.,Raman, M.C.C.,Hayes, C.,Lupardus, P.,Cole, D.K.,Harper, S.
T cell receptor interactions with human leukocyte antigen govern indirect peptide selectivity for the cancer testis antigen MAGE-A4.
J.Biol.Chem., 295:11486-11494, 2020

PubMed Abstract: T cell-mediated immunity is governed primarily by T cell receptor (TCR) recognition of peptide-human leukocyte antigen (pHLA) complexes and is essential for immunosurveillance and disease control. This interaction is generally stabilized by interactions between the HLA surface and TCR germline-encoded complementarity-determining region (CDR) loops 1 and 2, whereas peptide selectivity is guided by direct interactions with the TCR CDR3 loops. Here, we solved the structure of a newly identified TCR in complex with a clinically relevant peptide derived from the cancer testis antigen melanoma antigen-A4 (MAGE-A4). The TCR bound pHLA in a position shifted toward the peptide's N terminus. This enabled the TCR to achieve peptide selectivity via an indirect mechanism, whereby the TCR sensed the first residue of the peptide through HLA residue Trp-167, which acted as a tunable gateway. Amino acid substitutions at peptide position 1 predicted to alter the HLA Trp-167 side-chain conformation abrogated TCR binding, indicating that this indirect binding mechanism is essential for peptide recognition. These findings extend our understanding of the molecular rules that underpin antigen recognition by TCRs and have important implications for the development of TCR-based therapies.

PubMed: 32532817
DOI: 10.1074/jbc.RA120.014016

実験手法

X-RAY DIFFRACTION (3 Å)