title: Two distinct HLA-A*0101-specific submotifs illustrate alternative peptide binding modes.
abstract: Previous studies have defined two different peptide binding motifs specific for HLA-A*0101. These motifs are characterized by the presence of tyrosine (Y) at the C-termini of 9-mer and 10-mer peptides, and either a small polar or hydrophobic (S, T, M) residue in position 2, or a negatively charged (D or E) residue in position 3. In this study, the structural requirements for peptide binding to A*0101 have been further analyzed by examining the binding capacity of large sets of peptides corresponding to naturally occurring sequences which bore one or the other of these two A*0101-specific motifs. By correlating the presence of specific residue types at each position along the peptide sequence with increased (or decreased) binding affinity, the prominent influence of secondary anchor residues was revealed. In most cases, the two anchors in positions 2 and 3 appear to act synergistically. With the exception of the DE3 submotif in 9-mer peptides, a positive role for aromatic residues in position 1 and the center of the peptide (positions 4 or 5 of 9- or 10-mer peptides, respectively), and proline at C-3, were also consistently detected. However, secondary anchor residues also appear to differ significantly between the two different submotifs, demonstrating that A*0101 can utilize alternative modes in binding its peptide ligands. According to these analyses, specific refined submotifs were also established, and their merit verified by independent sets of potential A*0101 binding peptides. Besides providing useful insight into the nature of the interaction of the A*0101 allele with its peptide ligands, such refined motifs should also facilitate accurate prediction of potential A*0101-restricted peptide epitopes.
authors.affiliation: Takara Shuzo Co., Ltd., Biotechnology Research Laboratories, SETA 3-4-1, OTSU, SHIGA, 520-21, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kondo
authors.forename: J
authors.initials: J
authors.lastname: Sidney
authors.forename: S
authors.initials: S
authors.lastname: Southwood
authors.forename: M F
authors.initials: MF
authors.lastname: del Guercio
authors.forename: E
authors.initials: E
authors.lastname: Appella
authors.forename: H
authors.initials: H
authors.lastname: Sakamoto
authors.forename: H M
authors.initials: HM
authors.lastname: Grey
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.forename: R W
authors.initials: RW
authors.lastname: Chesnut
authors.forename: R T
authors.initials: RT
authors.lastname: Kubo
authors.forename: A
authors.initials: A
authors.lastname: Sette
mesh_terms: D001665:Binding Sites; D002461:Cell Line, Transformed; D015234:HLA-A Antigens / Q000276:immunology*; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D013329:Structure-Activity Relationship
chemical_list: D015234:HLA-A Antigens; D008024:Ligands; D010455:Peptides