5EU6

HLA Class I antigen

Summary for 5EU6

• Entry DOI: 10.2210/pdb5eu6/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, TYR-LEU-GLU-PRO-GLY-PRO-VAL-THR-VAL, ... (9 entities in total)
• Functional Keywords: immuno, hla-a02, 1e6-tcr, cross-reactivity, 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: 95854.94

Authors

Rizkallah, P.J.,Bianchi, V.,Cole, D.K.,Sewell, A.K. (deposition date: 2015-11-18, release date: 2016-03-02, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.02 Å)