title: Naturally occurring A pocket polymorphism in HLA-B*2703 increases the dependence on an accessory anchor residue at P1 for optimal binding of nonamer peptides.
abstract: Previous studies have shown the B*2703 subtype of HLA-B27, which differs from B*2705 and other MHC class I molecules by having a His substituted for Tyr at position 59 in the A pocket, inefficiently presents certain B*2705-restricted peptides. The current work investigates the influence of the first peptidic amino acid (P1) on peptide binding to B*2705 and B*2703. Results show P1 has a marked effect for both subtypes, with relative affinities (EC50) of P1-substituted peptides spanning four orders of magnitude. All peptides tested bind better to B*2705 than to B*2703. However, Lys, Arg, Phe, or Trp at P1 result in a < or = 2-fold difference between subtypes, while other amino acids produce greater differences (maximum approximately 50-fold for Leu). Self peptides eluted from B*2703, as well as two viral epitopes, have a motif similar to B*2705 peptides, except for a stronger preference for Lys or Arg at P1, consistent with peptide binding data. Computer modeling of B*2703 reveals movement of a water molecule and the alpha1 alpha-helix to allow His at position 59 to maintain important hydrogen bonds with the peptide N terminus in the A pocket. However, these bonds are weaker, and the water molecule movement results in the loss of a hydrogen bond with Glu-45 in the B pocket. We conclude that B*2703, as a consequence of its unique A pocket polymorphism, appears to have a greater dependency on an accessory anchor residue at P1 to maintain tight binding of peptides.
authors.affiliation: William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Griffin
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.forename: T
authors.initials: T
authors.lastname: Friede
authors.forename: S
authors.initials: S
authors.lastname: Stevanovic
authors.forename: K
authors.initials: K
authors.lastname: Ariyoshi
authors.forename: S L
authors.initials: SL
authors.lastname: Rowland-Jones
authors.forename: H G
authors.initials: HG
authors.lastname: Rammensee
authors.forename: R A
authors.initials: RA
authors.lastname: Colbert
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000378:metabolism; D001120:Arginine / Q000502:physiology; D003198:Computer Simulation; D000939:Epitopes / Q000378:metabolism; D015235:HLA-B Antigens / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D000939:Epitopes; D015235:HLA-B Antigens; D009842:Oligopeptides; D001120:Arginine