Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis

Autor: Julie E. Penzotti, Gerald T. Nepom, Terry P. Lybrand
Rok vydání: 1997
Předmět:
Zdroj: Arthritis & Rheumatism. 40:1316-1326
ISSN: 1529-0131
0004-3591
Popis: Objective. 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 DRβ chain. Methods. 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. Results. The predicted TCR-MHC-peptide complex involved multiple interactions and specificity for the shared epitope. TCR residues CDR1β D30, CDR2β N51, and CDR3β Q97 were positioned to potentially participate in hydrogen bond interactions with the shared epitope DRβ residues Q70 and R71. Conclusion. These results suggest a structural mechanism in which specific TCR recognition and possibly Vβ selection are directly influenced by the disease-associated MHC polymorphisms.
Databáze: OpenAIRE
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