X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II.
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.
Dessen
A
A
Laboratory of Molecular Medicine, The Children's Hospital, Boston, Massachusetts 02115, USA. dessen@xtal22.tch.harvard.edu
Lawrence
C M
CM
Cupo
S
S
Zaller
D M
DM
Wiley
D C
DC
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology; D001665:Binding Sites; D003094:Collagen / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure; D018360:Crystallography, X-Ray; D019281:Dimerization; D004768:Enterotoxins / Q000737:chemistry; D018604:Epitope Mapping; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000648:ultrastructure*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins; D018089:Superantigens / Q000737:chemistry
D004768:Enterotoxins; D015804:HLA-DR4 Antigen; D010455:Peptides; D011994:Recombinant Proteins; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D003094:Collagen