The autoimmune TCR-Ob 2F3 can bind to MBP85-99/HLA-DR2 having an unconventional mode as in TCR-Ob 1A12

Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02193, USA.
Molecular Immunology (Impact Factor: 2.97). 11/2010; 48(1-3):314-20. DOI: 10.1016/j.molimm.2010.07.010
Source: PubMed


The generation of T cell receptor (TCR) sequence diversity can produce 'forbidden' clones able to recognize self-antigens. Here, the structure of the complex between a myelin basic protein peptide (MBP85-99), human leukocyte antigen (HLA)-DR2 (DRB1*1501/DRA) and TCR-Ob.2F3, the dominant autoimmune clone obtained from a multiple sclerosis (MS) patient, has been determined using structural docking simulation and dynamics in silico and compared to the structure of TCR-Ob.1A12 complexes with the same MHC/peptide determined by X-ray crystallography. The two TCRs differ by three amino acids in the CDR3 α and β loops. As the result different hydrogen bonds are formed between the two CDR3β loops and the peptide in the complexes of the simulated structures, with three hydrogen bonds seen in the TCR-Ob.2F3 complex and five in the TCR-Ob.1A12 complex. The two TCRs, each located near the N-terminal end of the HLA-DR2 binding groove and both had an orthogonal binding axis but they deviated by about 10°. Simulation methods, such as structural docking and molecular dynamics as used here, provide an avenue to understand molecular binding mode efficiently and more rapidly than obtaining multiple crystal structures when a large structural database is already available.

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    • "d that portion of MHCII which surrounds that part of the peptide . Hence the TCR rotated is heavily tilted to - wards what is normally illustrated to be the left hand end of the MHC protein ( Fig . 2 ) . Recent work on TCRs , Ob . 2F3 and Ob . 3D1 , from one of the same donors indicated that these TCRs also bind the N terminal end of the peptide ( Kato et al . , 2010 ) . These TCRs may have low affinity for their self MHC / self peptide ligands , however , they may also escape tolerance mechanisms in the thymus because their angle of approach to MHC lowers the ability of CD4 to contribute to signaling within the T cell ( Adams et al . , 2011 ; Yin et al . , 2012a ) . Another version of engagement of"
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