Pii: S0167-5699(97)01238-3

binding motifs of major histocompatibility complex (MHC) proteins, originally discovered by pool sequencing of MHC class I-bound peptides1, provide a biochemical basis for the phenomenon of MHC restriction of T-cell responses. However, the analysis of class II peptide motifs has proved difficult due to the heterogeneity in peptide length2–4. This problem has been overcome using several approaches to characterize the binding motifs of human HLA-DR class II proteins (reviewed in Ref. 5). The understanding of the specificity of peptide–MHC class II interactions was greatly facilitated by the three-dimensional structures of HLA-DR1 (Ref. 6) and of its complex with a peptide7. Similar to class I molecules, the HLA-DR structure revealed pockets in the peptide-binding groove accommodating several ‘anchor’ residues in a peptide. The specificity of these pockets is influenced by polymorphic residues, resulting in allele-specific class II motifs. The consensus core sequence of peptides binding to HLA-DR appears to be a nonamer with anchor residues at positions 1, 4, 6 and 9 (Ref. 5). Position 1 (P1) appears critical for binding and is invariably occupied by either aromatic or aliphatic residues. In addition, the murine class II I-E molecules, which are closely homologous to HLA-DR, were shown to be similar in their structure8 and binding motifs9,10. The amino acid usage at the anchor positions in DR/I-E motifs seems to be more flexible than in class I motifs, allowing several possible residues at each position. Nevertheless, the overall combination of several positions results in a stringent binding motif. In contrast to the well-characterized DR/I-E motifs, the peptidebinding specificity of human HLA-DQ and particularly of the murine H-2A (I-A) MHC class II proteins is controversial.