Use of T cell receptor/HLA-DRB104 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis

• Published in: Arthritis and rheumatism Vol. 40; no. 7; p. 1316
• Main Authors: Penzotti, J E, Nepom, G T, Lybrand, T P
• Format: Journal Article
• Language: English
• Published: United States 01.07.1997
• Subjects: Amino Acid Sequence; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - immunology; Epitopes - chemistry; HLA-DR Antigens - chemistry; HLA-DR4 Antigen - immunology; HLA-DRB1 Chains; Humans; Major Histocompatibility Complex - genetics; Models, Molecular; Molecular Sequence Data; Polymorphism, Genetic; Receptors, Antigen, T-Cell - chemistry; Sequence Alignment; T-Lymphocytes - immunology
• ISSN: 0004-3591
• DOI: 10.1002/1529-0131(199707)40:7<1316::AID-ART17>3.0.CO;2-I

To use molecular modeling tools to analyze the potential structural 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 region of the DRbeta chain. Homology model building techniques were used to construct molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor (TCR) from T cell clone EM025, which is specific for DR4 molecules containing the shared epitope sequence. Interactive graphics techniques were used to orient the TCR on the DR molecule, guided by surface complementarity analysis. The predicted TCR-MHC-peptide complex involved multiple interactions and specificity for the shared epitope. TCR residues CDR1beta D30, CDR2beta N51, and CDR3beta Q97 were positioned to potentially participate in hydrogen bond interactions with the shared epitope DRbeta residues Q70 and R71. These results suggest a structural mechanism in which specific TCR recognition and possibly Vbeta selection are directly influenced by the disease-associated MHC polymorphisms.