Modeling the ternary complex TCR-Vbeta/CollagenII(261-273)/HLA-DR4 associated with rheumatoid arthritis.

PloS One
Maria Cristina De RosaFrancesco Ria

Abstract

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. 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...Continue Reading

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Nov 2, 2011·Internal and Emergency Medicine·Gianfranco Ferraccioli, Elisa Gremese
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Apr 19, 2019·ACS Medicinal Chemistry Letters·Francesco RiaMaria Cristina De Rosa

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Methods Mentioned

BETA
PCR

Software Mentioned

Verify3D
NACCESS
GROMOS96
Discovery
CHARMM
VERIFY
BLAST
ExPASy Proteomics Server
FTDOCK
PROCHECK

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