5EU3

HLA Class I antigen

5EU3 の概要

• エントリーDOI: 10.2210/pdb5eu3/pdb
• 分子名称: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, GP100 peptide YLEPGPVTA, ... (6 entities in total)
• 機能のキーワード: immuno, hla-a02, 1e6-tcr, cross-reactivity, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P01892; Secreted : P61769
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 45022.98

構造登録者

Rizkallah, P.J.,Bianchi, V.,Cole, D.K.,Sewell, A.K. (登録日: 2015-11-18, 公開日: 2016-03-02, 最終更新日: 2024-11-06)

主引用文献

Bianchi, V.,Bulek, A.,Fuller, A.,Lloyd, A.,Attaf, M.,Rizkallah, P.J.,Dolton, G.,Sewell, A.K.,Cole, D.K.
A Molecular Switch Abrogates Glycoprotein 100 (gp100) T-cell Receptor (TCR) Targeting of a Human Melanoma Antigen.
J.Biol.Chem., 291:8951-8959, 2016

PubMed Abstract: Human CD8(+) cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective. The melanocyte differentiation protein, glycoprotein 100 (gp100), encodes a naturally processed epitope that is an attractive target for melanoma immunotherapies, in particular peptide-based vaccines. Previous studies have shown that substitutions at peptide residue Glu(3) have a broad negative impact on polyclonal T-cell responses. Here, we describe the first atomic structure of a natural cognate TCR in complex with this gp100 epitope and highlight the relatively high affinity of the interaction. Alanine scan mutagenesis performed across the gp100(280-288) peptide showed that Glu(3) was critically important for TCR binding. Unexpectedly, structural analysis demonstrated that the Glu(3) → Ala substitution resulted in a molecular switch that was transmitted to adjacent residues, abrogating TCR binding and T-cell recognition. These findings help to clarify the mechanism of T-cell recognition of gp100 during melanoma responses and could direct the development of altered peptides for vaccination.

PubMed: 26917722
DOI: 10.1074/jbc.M115.707414

実験手法

X-RAY DIFFRACTION (1.97 Å)