X-RAY CRYSTAL-STRUCTURE OF HLA-DR4 (DRA-ASTERISK-0101, DRB1-ASTERISK-0401) COMPLEXED WITH A PEPTIDE FROM HUMAN COLLAGEN-II

Genetic predisposition to rheumatoid arthritis (RA) is linked to the M HC class II allele HLA-DR4. The charge of the amino acid at DR beta 71 in the peptide-binding site appears to be critical in discriminating DR molecules linked to increased disease susceptibility. We have deter mined the 2.5 Angstrom x-ray structure of the DR4 molecule with the st rongest linkage to RA (DRB10401) complexed with a human collagen II p eptide. Details of a predicted salt bridge between lysine DR beta 71 a nd aspartic acid at the P4 peptide position suggest how it may partici pate in both antigen binding and TCR activation. A model is proposed f or the DR4 recognition of collagen II (261-273), an antigen immunodomi nant in human-transgenic mouse models of RA.