Structure-based design of nonnatural ligands for the HLA-B27 protein

X-ray studies as well as structure-activity relationships indicate that the central part of class I MHC-binding nonapeptides represents the main inter action site for a T cell receptor. In order to rationally manipulate T cell epitopes, several nonpeptidic spacer have been designed from the X-ray str ucture of a MHC-peptide complex and substituted for the T cell receptor-bin ding part of several antigenic peptides. The binding of the modified epitop es to the HLA-B*2705 protein was studied by an in vitro stabilisation assay and the thermal stability of all complexes examined by circular dichroism spectroscopy. Depending on their chemical nature and length, the introduced spacers may be classified into two categories. Monofunctional spacers (11- amino undecanoate, (R)-3-hydroxybutyrate trimer) simply link two anchoring peptide positions (P3 and P9) but loosely contact the MHC binding groove, a cid thus decrease more or less the affinity of the altered epitopes to HLA- B*2705. Bifunctional spacers ((R)-3-hydroxybutyrate and beta-homoalanine co mbinations) not only bridges the two distant anchoring amino acids but also strongly interact with the binding cleft and lead to an increase in bindin g to the MHC protein. The presented modified ligands constitute interesting tools for perturbing the T cell response to the parent antigenic peptide.