USE OF T-CELL RECEPTOR HLA-DRB1-ASTERISK-04 MOLECULAR MODELING TO PREDICT SITE-SPECIFIC INTERACTIONS FOR THE DR SHARED EPITOPE ASSOCIATED WITH RHEUMATOID-ARTHRITIS

Objective. To use molecular modeling tools to analyze the potential st ructural basis for the genetic association of rheumatoid arthritis (RA ) with the major histocompatibility complex (MHC) ''shared epitope,'' a set of conserved amino acid residues in the third hypervariable regi on of the DR beta chain. Methods. Homology model building techniques w ere used to construct molecular models of the arthritis-associated DRB 10404 molecule and a T cell receptor (TCR) from T cell clone EM025, w hich is specific for DR4 molecules containing the shared epitope seque nce. Interactive graphics techniques were used to orient the TCR on th e DR molecule, guided by surface complementarity analysis. Results. Th e predicted TCR-MHC-peptide complex involved multiple interactions and specificity for the shared epitope. TCR residues CDR1 beta D30, CDR2 beta N51, and CDR3 beta Q97 were positioned to potentially participate in hydrogen bond interactions with the shared epitope DR beta residue s Q70 and R71. Conclusion. These results suggest a structural mechanis m in which specific TCR recognition and possibly V-beta selection are directly influenced by the disease-associated MHC polymorphisms.