title: Modeling the ternary complex TCR-Vbeta/CollagenII(261-273)/HLA-DR4 associated with rheumatoid arthritis.
abstract: 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.
  
  
  RESULTS
  Here we have used computational modeling to get insight into this interaction. A three-dimensional model of the TCR Vbeta domain from a DR4(+) patient affected by RA has been derived by homology modeling techniques. Subsequently, the structure of the TCR Vbeta 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 CDR3beta 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
  This work presents a three-dimensional model for the ternary complex TCR-Vbeta/collagenII(261-273)/HLA-DR4 associated with rheumatoid arthritis that can provide insights into the molecular mechanisms of self reactivity.
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Rome, Italy. mariacristina.derosa@icrm.cnr.it
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: De Rosa
authors.forename: Bruno
authors.initials: B
authors.lastname: Giardina
authors.forename: Caterina
authors.initials: C
authors.lastname: Bianchi
authors.forename: Cristiana
authors.initials: C
authors.lastname: Carelli Alinovi
authors.forename: Davide
authors.initials: D
authors.lastname: Pirolli
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Ferraccioli
authors.forename: Maria
authors.initials: M
authors.lastname: De Santis
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Sante
authors.forename: Francesco
authors.initials: F
authors.lastname: Ria
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*
chemical_list: D024043:Collagen Type II; D015804:HLA-DR4 Antigen; D011948:Receptors, Antigen, T-Cell