Structural principles that govern the peptide-binding motifs of class I MHC molecules.

The peptides that bind class I MHC molecules are restricted in length and often contain key amino acids, anchor residues, at particular positions. The side-chains of peptide anchor residues interact with the polymorphic complementary pockets in MHC peptide-binding grooves and provide the molecular basis for allele-specific recognition of antigenic peptides. We establish correlations between class I MHC specificities for anchor residues and class I MHC sequence markers that occur at the polymorphic positions lining the structural pockets. By analyzing the pocket structures of nine crystallized class I MHC molecules and the modeled structures of another 39 class I MHC molecules, we show that class I pockets can be classified into families that are distinguishable by their common physico-chemical properties and peptide side-chain selectivities. The identification of recurrent structural principles among class I pockets makes it possible to greatly expand the repertoire of known peptide-binding motifs of class I MHC molecules. The evolutionary strategies underlying the emergence of pocket families is briefly discussed.