Analysis of the structure of naturally processed peptides bound by class I and class II major histocompatibility complex molecules.

Antigen-specific T-cell responses require antigenic peptides presented on the cell surface by the major histocompatibility complex (MHC) molecules. The structural characteristics of these peptides are being defined. It is now known that the majority of peptides that associate with MHC Class I are 8-10 residues long, with allotype-specific binding motifs containing up to three anchor positions. This is consistent with the presence of six pockets and the close-ended structure of the MHC Class I peptide binding groove. In contrast to peptides associated with MHC Class I, those associated with MHC Class II are 10-34 residues in length and are commonly presented in nested sets with extensions or truncations at the N- or C-terminal ends. Binding motifs for MHC Class II appear to contain up to four anchor positions, with more loosely defined amino acid preferences. The expression of histocompatibility proteins in cells that do not load peptides but fold them correctly has permitted the X-ray analysis of the three-dimensional structure of Class I and Class II complexes with single defined peptides. The differences in length between the Class I and Class II sequences can be ascribed to small structural differences between the two binding sites and the positioning of key residues, that make hydrogen bonds to the bound peptides. Recent advances in mass spectrometry are making possible the analysis and sequencing of subpicomolar quantities of MHC-bound peptides and the estimation of the size of the total population of peptides. The sequence information derived from this technique, in conjunction with X-ray crystallographic analysis of MHC complexes involving single, defined peptides, may provide a new approach towards the development of useful reagents for therapeutic intervention.