A tricyclic ring system replaces the variable regions of peptides presented by three alleles of human MHC class I molecules.
BACKGROUND
Cytotoxic T-lymphocytes (CTLs) recognize complexes of short peptides with major histocompatibility complex (MHC) class I molecules. MHC molecules are polymorphic, and the products of different MHC alleles bind to different subsets of peptides. This is due to differences in the shape of the peptide-binding groove on the surface of the MHC protein, especially the 'pockets' into which anchor residues at each end of the peptide fit. Non-peptidic ligands for class I molecules may be useful clinically.


RESULTS
By applying computer-aided design methods guided by X-ray structures, we designed and synthesized several MHC class I ligands, based on known peptide ligands, in which the tricyclic, aromatic compound phenanthridine replaced the central amino acids of the peptides. These semi-peptidic fluorescent ligands bound with high affinity and with allelic specificity to the peptide-binding groove of different MHC class I molecules, forming crystallizable complexes.


CONCLUSIONS
Specificity for binding to different MHC class I molecules can be imparted to the common phenanthridine element by judicious choice of terminal peptidic elements from either nonamer or decamer peptides. The phenanthridine-based ligands have a long bound half-life, as do antigenic peptides.
Weiss
G A
GA
Department of Chemistry, Harvard University, Cambridge, MA 02138, USA.
Collins
E J
EJ
Garboczi
D N
DN
Wiley
D C
DC
Schreiber
S L
SL
D000483:Alleles; D002942:Circular Dichroism; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D005805:Genes, MHC Class I / Q000235:genetics*; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D010617:Phenanthridines; D017510:Protein Folding; D013696:Temperature
D015395:Histocompatibility Antigens Class I; D008024:Ligands; C098080:MICB antigen; D010455:Peptides; D010617:Phenanthridines