Substituting nonpeptidic spacers for the T cell receptor-binding part of class I major histocompatibility complex-binding peptides.
X-ray diffraction studies as well as structure-activity relationships indicate that the central part of class I major histocompatibility complex (MHC)-binding nonapeptides represents the main interaction site for a T cell receptor. In order to rationally manipulate T cell epitopes, three nonpeptidic spacers have been designed from the x-ray structure of a MHC-peptide complex and substituted for the T cell receptor-binding part of several antigenic peptides. The binding of the modified epitopes to the human leukocyte antigen-B*2705 protein was studied by an in vitro stabilization assay, and the thermal stability of all complexes was 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 and thus decrease more or less the affinity of the altered epitopes to human leukocyte antigen-B*2705. A bifunctional spacer ((R)-3-hydroxybutyrate tetramer) not only bridges the two distant anchoring amino acids but also strongly interacts with the binding cleft and leads to a 5-fold increase in binding to the MHC protein. To our knowledge, this is the first report of a nonpeptidic modification of T-cell receptor binding residues that significantly enhances the binding of altered peptide ligands to their host MHC protein. The presented modified ligands constitute interesting tools for perturbing the T cell response to the parent antigenic peptide.
Department of Pharmacy, Swiss Federal Institute of Technology, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
S
S
Krebs
J R
JR
Lamas
S
S
Poenaru
G
G
Folkers
J A
JA
de Castro
D
D
Seebach
D
D
Rognan
D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D015796:HLA-B27 Antigen / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D011489:Protein Denaturation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D055672:Static Electricity; D013329:Structure-Activity Relationship
D015796:HLA-B27 Antigen; D008024:Ligands; D011948:Receptors, Antigen, T-Cell