DISTINCT CONFORMATIONS OF A PEPTIDE BOUND TO HLA-DR1 OR DRB5-ASTERISK-0101 SUGGESTED BY MOLECULAR MODELING

The conformation of peptides when bound to different HLA class II mole cules is of interest in the study of specificity and function of respo nding T cells. Here, we report the investigation of the HLA-DR binding profiles of an immunodominant and HLA promiscuous mycobacterial pepti de, p38G. Its binding affinities were found to be high for DR1, modera te for DR2, DR7 and DR8, low for DR4, DR5, DR6 and DR9, and below dete ction for DR3. The minimum peptide length required for binding was, in the majority of cases, nine residues and 11 in two instances (DR2 and DR4). Peptide binding to DR2 was attributed to the DRB50101 and not to the DRB11501 gene product. Substitution analysis of the amino acid residues involved in binding to DR1 and DRB50101 identified F-354 as the common primary contact residue (P1), while allele-specific differ ences were found in positions P4, P6 and in the C-terminal anchor resi due (valine at P9 for DR1 or lysine at P10 for DRB50101). Computer-as sisted evaluation of these empirical data produced a molecular model, suggesting that the peptide binds to DR1 in an elongated conformation, similar to that of other peptide MHC class II complexes. In contrast, the DRB50101 bound peptide is likely to be kinked, which so far was considered characteristic only for peptides within MHC class I complex es. The different conformations imposed on the same peptide by distinc t HLA alleles may represent an important mechanism for the control of T cell responses.