Rational design of nonnatural peptides as high-affinity ligands for the HLA-B*2705 human leukocyte antigen.
From the three-dimensional structure of the class I major histocompatibility complex (MHC) HLA-B*2705 protein, several nonnatural peptides were designed either to optimize the interactions of one peptide amino acid (position 3) with its HLA binding pocket (pocket D) or to simplify the T-cell receptor-binding part by substitution with organic spacers. The stability of each MHC-ligand complex was simulated by 150-ps molecular dynamics in a water environment and compared with that of the natural complexes. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro assembly assay. As predicted from the computed atomic fluctuations and buried surface areas of MHC-bound ligands, bulky hydrophobic side chains at position 3 enhance the binding of a nonameric peptide to the HLA-B27 protein. Furthermore, it was possible to simplify half of the peptide sequence (residues 4-8) by replacement with organic fragments without altering the affinity of the designed ligands for the class I MHC protein. This study constitutes an initial step toward the rational design of nonpeptide class I MHC ligands for use in the selective immunotherapy of autoimmune diseases associated with particular HLA alleles.
Department of Pharmacy, Swiss Federal Institute of Technology, Zürich.
D
D
Rognan
L
L
Scapozza
G
G
Folkers
A
A
Daser
D000595:Amino Acid Sequence; D001402:B-Lymphocytes; D016827:CD8 Antigens / Q000502:physiology; D002460:Cell Line; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D016827:CD8 Antigens; D015796:HLA-B27 Antigen; D008024:Ligands; D009842:Oligopeptides; D014867:Water