title: The class II MHC protein HLA-DR1 in complex with an endogenous peptide: implications for the structural basis of the specificity of peptide binding.
abstract: BACKGROUND
  Class II major histocompatibility complex (MHC) proteins are cell surface glycoproteins that bind peptides and present them to T cells as part of the mechanism for detecting and responding to foreign material in the body. The peptide-binding activity exhibits allele-specific preferences for particular sidechains at some positions, although the structural basis of these preferences is not understood in detail. We have determined the 2.45 A crystal structure of the human class II MHC protein HLA-DR1 in complex with the tight binding endogenous peptide A2 (103-117) in order to discover peptide-MHC interactions that are important in determining the binding motif and to investigate conformational constraints on the bound peptide.
  
  
  RESULTS
  The bound peptide adopts a polyproline II-like conformation and places several sidechains within pockets in the binding site. Bound water molecules mediate MHC-peptide contacts at several sites. A tryptophan residue from the beta 2 'lower' domain of HLA-DR1 was found to project into a pocket underneath the peptide-binding domain and may be important in modulating interdomain interactions in MHC proteins.
  
  
  CONCLUSIONS
  The peptide-binding motif of HLA-DR1 includes an aromatic residue at position +1, an arginine residue at position +2, and a small residue at position +6 (where the numbering refers to the normal MHC class II convention); these preferences can be understood in light of interactions observed in the peptide-MHC complex. Comparison of the structure with that of another MHC-peptide complex shows that completely different peptide sequences bind in essentially the same conformation and are accommodated with only minimal rearrangement of HLA-DR1 residues. Small conformational differences that are observed appear to be important in interactions with other proteins.
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD 21210, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Murthy
authors.forename: L J
authors.initials: LJ
authors.lastname: Stern
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D014867:Water / Q000737:chemistry
chemical_list: D015798:HLA-DR1 Antigen; D010455:Peptides; D014867:Water; C011083:polyproline