4WJ5

Structure of HLA-A2 in complex with an altered peptide ligands based on Mart-1 variant epitope

Summary for 4WJ5

• Entry DOI: 10.2210/pdb4wj5/pdb
• Descriptor: HLA class I histocompatibility antigen, A-2 alpha chain, Beta-2-microglobulin, Melanoma antigen recognized by T-cells 1, ... (5 entities in total)
• Functional Keywords: antigen presentation, major histocompatibility complex, hla-a2 antigen, altered peptide ligand, immune system
• Biological source: Homo sapiens (Human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P01892; Secreted : P61769; Endoplasmic reticulum membrane; Single-pass type III membrane protein: Q16655
• Total number of polymer chains: 6
• Total formula weight: 90634.70

Authors

Celie, P.H.N.,Rodenko, B.,Ovaa, H. (deposition date: 2014-09-29, release date: 2014-10-29, Last modification date: 2024-10-09)

Primary citation

Hoppes, R.,Oostvogels, R.,Luimstra, J.J.,Wals, K.,Toebes, M.,Bies, L.,Ekkebus, R.,Rijal, P.,Celie, P.H.,Huang, J.H.,Emmelot, M.E.,Spaapen, R.M.,Lokhorst, H.,Schumacher, T.N.,Mutis, T.,Rodenko, B.,Ovaa, H.
Altered Peptide Ligands Revisited: Vaccine Design through Chemically Modified HLA-A2-Restricted T Cell Epitopes.
J Immunol., 193:4803-4813, 2014

PubMed Abstract: Virus or tumor Ag-derived peptides that are displayed by MHC class I molecules are attractive starting points for vaccine development because they induce strong protective and therapeutic cytotoxic T cell responses. In thus study, we show that the MHC binding and consequent T cell reactivity against several HLA-A*02 restricted epitopes can be further improved through the incorporation of nonproteogenic amino acids at primary and secondary anchor positions. We screened more than 90 nonproteogenic, synthetic amino acids through a range of epitopes and tested more than 3000 chemically enhanced altered peptide ligands (CPLs) for binding affinity to HLA-A*0201. With this approach, we designed CPLs of viral epitopes, of melanoma-associated Ags, and of the minor histocompatibility Ag UTA2-1, which is currently being evaluated for its antileukemic activity in clinical dendritic cell vaccination trials. The crystal structure of one of the CPLs in complex with HLA-A*0201 revealed the molecular interactions likely responsible for improved binding. The best CPLs displayed enhanced affinity for MHC, increasing MHC stability and prolonging recognition by Ag-specific T cells and, most importantly, they induced accelerated expansion of antitumor T cell frequencies in vitro and in vivo as compared with the native epitope. Eventually, we were able to construct a toolbox of preferred nonproteogenic residues with which practically any given HLA-A*02 restricted epitope can be readily optimized. These CPLs could improve the therapeutic outcome of vaccination strategies or can be used for ex vivo enrichment and faster expansion of Ag-specific T cells for transfer into patients.

PubMed: 25311806
DOI: 10.4049/jimmunol.1400800

Experimental method

X-RAY DIFFRACTION (1.65 Å)