Crystal structures of two closely related but antigenically distinct HLA-A2/melanocyte-melanoma tumor-antigen peptide complexes

J Immunol. 2001 Sep 15;167(6):3276-84. doi: 10.4049/jimmunol.167.6.3276.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antigens, Neoplasm / chemistry*
  • Antigens, Neoplasm / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • HLA-A2 Antigen / chemistry*
  • HLA-A2 Antigen / metabolism
  • Humans
  • MART-1 Antigen
  • Macromolecular Substances
  • Melanoma / immunology
  • Models, Molecular
  • Neoplasm Proteins / chemistry*
  • Neoplasm Proteins / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Pliability
  • Protein Binding
  • Protein Conformation
  • T-Lymphocytes, Cytotoxic / immunology
  • Water

Substances

  • Antigens, Neoplasm
  • HLA-A2 Antigen
  • MART-1 Antigen
  • MLANA protein, human
  • Macromolecular Substances
  • Neoplasm Proteins
  • Peptide Fragments
  • Water

Associated data

  • PDB/1JF1
  • PDB/1JHT