Crystal structures of two closely related but antigenically distinct HLA-A2/melanocyte-melanoma tumor-antigen peptide complexes.
We have determined high-resolution crystal structures of the complexes of HLA-A2 molecules with two modified immunodominant peptides from the melanoma tumor-associated protein Melan-A/Melanoma Ag recognized by T cells-1. The two peptides, a decamer and nonamer with overlapping sequences (ELAGIGILTV and ALGIGILTV), are modified in the second residue to increase their affinity for HLA-A2. The modified decamer is more immunogenic than the natural peptide and a candidate for peptide-based melanoma immunotherapy. The crystal structures at 1.8 and 2.15 A resolution define the differences in binding modes of the modified peptides, including different clusters of water molecules that appear to stabilize the peptide-HLA interaction. The structures suggest both how the wild-type peptides would bind and how three categories of cytotoxic T lymphocytes with differing fine specificity might recognize the two peptides.
Sliz
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Department of Molecular and Cellular Biology and Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Michielin
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Cerottini
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JC
Luescher
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Romero
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Karplus
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M
Wiley
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DC
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D058965:MART-1 Antigen; D046911:Macromolecular Substances; D008545:Melanoma / Q000276:immunology; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D018583:Pliability; D011485:Protein Binding; D011487:Protein Conformation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014867:Water
D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D014867:Water