Distinct conformations of a peptide bound to HLA-DR1 or DRB5*0101 suggested by molecular modelling.
The conformation of peptides when bound to different HLA class II molecules is of interest in the study of specificity and function of responding T cells. Here, we report the investigation of the HLA-DR binding profiles of an immunodominant and HLA-promiscuous mycobacterial peptide, p38G. Its binding affinities were found to be high for DR1, moderate for DR2, DR7 and DR8, low for DR4, DR5, DR6 and DR9, and below detection 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 DRB5*0101 and not to the DRB1*1501 gene product. Substitution analysis of the amino acid residues involved in binding to DR1 and DRB5*0101 identified F-354 as the common primary contact residue (P1), while allele-specific differences were found in positions P4, P6 and in the C-terminal anchor residue (valine at P9 for DR1 or lysine at P10 for DRB5*0101). Computer-assisted 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 DRB5*0101 bound peptide is likely to be kinked, which so far was considered characteristic only for peptides within MHC class I complexes. The different conformations imposed on the same peptide by distinct HLA alleles may represent an important mechanism for the control of T cell responses.
Jurcevic
S
S
Tuberculosis and Related Infections Unit, MRC Clinical Sciences Centre, Hammersmith Hospital, London, UK.
Travers
P J
PJ
Hills
A
A
Agrewala
J N
JN
Moreno
C
C
Ivanyi
J
J
D000483:Alleles; D006684:HLA-DR Antigens / Q000378:metabolism*; D015798:HLA-DR1 Antigen / Q000378:metabolism*; D059847:HLA-DRB5 Chains; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation
D006684:HLA-DR Antigens; D015798:HLA-DR1 Antigen; D059847:HLA-DRB5 Chains; D010455:Peptides