Modeling the Ternary Complex TCR-V beta/CollagenII(261-273)/HLA-DR4 Associated with Rheumatoid Arthritis

Gabriele Di Sante, Francesco Ria, Bruno Giardina, Caterina Bianca Neve Aurora Bianchi, Cristiana Carelli Alinovi, Davide Pirolli, Gianfranco Ferraccioli, Maria De Santis, Mc De Rosa

Risultato della ricerca: Contributo in rivistaArticolo in rivista

26 Citazioni (Scopus)


Background: It is known that genetic predisposition to rheumatoid arthritis (RA) is associated with the MHC class II allele HLA-DR4 and that residues 261-273 of type II collagen (huCollp261) represent an immunodominant T cell epitope restricted by the DR4 molecule. Despite recent advances in characterization of MHC and T cell receptor (TCR) contacts to this epitope, the atomic details of TCR/huCollp261/HLA-DR4 ternary complex are not known. Methodology/Principal Findings: Here we have used computational modeling to get insight into this interaction. A three-dimensional model of the TCR V beta domain from a DR4(+) patient affected by RA has been derived by homology modeling techniques. Subsequently, the structure of the TCR V beta domain in complex with huCollp261/HLA-DR4 was obtained from a docking approach in conjunction with a filtering procedure based on biochemical information. The best complex from the docking experiments was then refined by 20 ns of molecular dynamics simulation in explicit water. The predicted model is consistent with available experimental data. Our results indicate that residues 97-101 of CDR3 beta are critical for recognition of huCollp261/HLA-DR4 by TCR. We also show that TCR contacts on p/MHC surface affect the conformation of the shared epitope expressed by DR alleles associated with RA susceptibility. Conclusions/Significance: This work presents a three-dimensional model for the ternary complex TCR-V beta/collagenII(261-273)/HLA-DR4 associated with rheumatoid arthritis that can provide insights into the molecular mechanisms of self reactivity
Lingua originaleEnglish
pagine (da-a)N/A-N/A
RivistaPLoS One
Stato di pubblicazionePubblicato - 2010



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