title: The autoimmune TCR-Ob.2F3 can bind to MBP85-99/HLA-DR2 having an unconventional mode as in TCR-Ob.1A12.
abstract: 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.
authors.affiliation: Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02193, USA. zenkato@mac.com
authors.forename: Zenichiro
authors.initials: Z
authors.lastname: Kato
authors.forename: Joel N H
authors.initials: JN
authors.lastname: Stern
authors.forename: Hironori K
authors.initials: HK
authors.lastname: Nakamura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miyashita
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kuwata
authors.forename: Naomi
authors.initials: N
authors.lastname: Kondo
authors.forename: Jack L
authors.initials: JL
authors.lastname: Strominger
mesh_terms: D001324:Autoantigens / Q000737:chemistry* / Q000276:immunology; D018360:Crystallography, X-Ray; D015802:HLA-DR2 Antigen / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods*; D008961:Models, Structural; D009103:Multiple Sclerosis / Q000276:immunology; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology; D020836:Protein Structure, Quaternary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology
chemical_list: D001324:Autoantigens; D015802:HLA-DR2 Antigen; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C107908:myelin basic protein 85-99