X-ray crystal structure of HLA-DR4 (DRA0101, DRB10401) complexed with a peptide from human collagen II

• Published in: Immunity (Cambridge, Mass.) Mass.), 1997-10, Vol.7 (4), p.473-481
• Main Authors: Dessen, A, Lawrence, C M, Cupo, S, Zaller, D M, Wiley, D C
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Animals; Arthritis, Rheumatoid - immunology; Binding Sites; Collagen - chemistry; Collagen - immunology; Collagen - ultrastructure; Crystallography, X-Ray; Dimerization; Enterotoxins - chemistry; Epitope Mapping; HLA-DR4 Antigen - genetics; HLA-DR4 Antigen - ultrastructure; Humans; Mice; Mice, Transgenic; Models, Molecular; Peptides - chemistry; Peptides - immunology; Protein Conformation; Protein Structure, Tertiary; Recombinant Proteins; Superantigens - chemistry
• ISSN: 1074-7613
• DOI: 10.1016/S1074-7613(00)80369-6

Genetic predisposition to rheumatoid arthritis (RA) is linked to the MHC class II allele HLA-DR4. The charge of the amino acid at DRbeta71 in the peptide-binding site appears to be critical in discriminating DR molecules linked to increased disease susceptibility. We have determined the 2.5 A x-ray structure of the DR4 molecule with the strongest linkage to RA (DRB1*0401) complexed with a human collagen II peptide. Details of a predicted salt bridge between lysine DRbeta71 and aspartic acid at the P4 peptide position suggest how it may participate in both antigen binding and TCR activation. A model is proposed for the DR4 recognition of collagen II (261-273), an antigen immunodominant in human-transgenic mouse models of RA.