PDBsum entry 1ymm

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Immune system PDB id
Protein chains
182 a.a. *
178 a.a. *
14 a.a. *
96 a.a. *
246 a.a. *
* Residue conservation analysis
PDB id:
Name: Immune system
Title: Tcr/hla-dr2b/mbp-peptide complex
Structure: Hla class ii histocompatibility antigen, dr alpha chain: a. Synonym: hla-dr2b alpha. Engineered: yes. Hla class ii histocompatibility antigen, dr beta chain: b. Synonym: hla-dr2b beta. Engineered: yes. Mbp peptide.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-dra. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Synthetic: yes.
Biol. unit: Pentamer (from PQS)
3.50Å     R-factor:   0.274     R-free:   0.318
Authors: M.Hahn,M.J.Nicholson,J.Pyrdol,K.W.Wucherpfennig
Key ref:
M.Hahn et al. (2005). Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat Immunol, 6, 490-496. PubMed id: 15821740 DOI: 10.1038/ni1187
21-Jan-05     Release date:   03-May-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P01903  (DRA_HUMAN) -  HLA class II histocompatibility antigen, DR alpha chain
254 a.a.
182 a.a.
Protein chain
Pfam   ArchSchema ?
P01911  (2B1F_HUMAN) -  HLA class II histocompatibility antigen, DRB1-15 beta chain
266 a.a.
178 a.a.
Protein chain
Pfam   ArchSchema ?
P02686  (MBP_HUMAN) -  Myelin basic protein
304 a.a.
14 a.a.
Protein chain
Pfam   ArchSchema ?
P01848  (TCA_HUMAN) -  T-cell receptor alpha chain C region
142 a.a.
96 a.a.*
Protein chain
Pfam   ArchSchema ?
P01850  (TRBC1_HUMAN) -  T-cell receptor beta-1 chain C region
177 a.a.
246 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 70 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   2 terms 
  Biological process     immune response   2 terms 


DOI no: 10.1038/ni1187 Nat Immunol 6:490-496 (2005)
PubMed id: 15821740  
Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor.
M.Hahn, M.J.Nicholson, J.Pyrdol, K.W.Wucherpfennig.
Autoimmune diseases are caused by self-reactive lymphocytes that have escaped deletion. Here we have determined the structure of the trimolecular complex for a T cell receptor (TCR) from a patient with multiple sclerosis that causes autoimmunity in transgenic mice. The structure showed a TCR topology notably different from that of antimicrobial TCRs. Rather than being centered on the peptide-major histocompatibility complex, this TCR contacted only the N-terminal peptide segment and made asymmetrical interactions with the major histocompatibility complex helices. The interaction was dominated by the hypervariable complementarity-determining region 3 loops, indicating that unconventional topologies are possible because of the unique complementarity-determining region 3 sequences created during rearrangement. This topology reduces the interaction surface with peptide and alters the geometry for CD4 association. We propose that unusual TCR-binding properties can permit autoreactive T cells to escape deletion.
  Selected figure(s)  
Figure 2.
Figure 2. Footprint of the Ob.1A12 TCR on the MBP peptide-DR2 surface. The Ob.1A12 TCR contacts only the N-terminal segment of the MBP peptide. The TCR CDR3 and CDR3 loops (yellow and red, respectively) dominate the interaction and converge over peptide residue P2 His. The CDR3 loop also contacts a histidine from the DR chain helix (DR 81 His). The CDR1 and CDR2 loops of TCR (green and cyan, respectively) and TCR (purple and pink, respectively) cover smaller surface areas.
Figure 7.
Figure 7. Consequence of altered topology on the geometry of CD4 coreceptor engagement. The variable domains of the Ob.1A12 (a) and HA1.7 (b) TCRs were superimposed. The relative position of the peptide-MHC component in the two trimolecular complexes is presented. The CD4 coreceptor binds to the membrane-proximal MHC 2 and 2 domains under the -sheet of the peptide-binding site, as shown for the complex of a mouse MHC class II molecule and CD4 (c; D1 and D2 domains; green, CD4 molecule; gray, MHC molecule^33). The MHC-bound peptide is yellow in all structures.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Immunol (2005, 6, 490-496) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21199956 D.K.Sethi, D.A.Schubert, A.K.Anders, A.Heroux, D.A.Bonsor, C.P.Thomas, E.J.Sundberg, J.Pyrdol, and K.W.Wucherpfennig (2011).
A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC.
  J Exp Med, 208, 91.
PDB code: 3pl6
21364947 J.M.Khan, and S.Ranganathan (2011).
Understanding TR Binding to pMHC Complexes: How Does a TR Scan Many pMHC Complexes yet Preferentially Bind to One.
  PLoS One, 6, e17194.  
21306912 K.W.Wucherpfennig, and D.Sethi (2011).
T cell receptor recognition of self and foreign antigens in the induction of autoimmunity.
  Semin Immunol, 23, 84-91.  
21297580 Y.Yin, Y.Li, M.C.Kerzic, R.Martin, and R.A.Mariuzza (2011).
Structure of a TCR with high affinity for self-antigen reveals basis for escape from negative selection.
  EMBO J, 30, 1137-1148.
PDB code: 3o6f
20489610 A.W.Michels, and M.Nakayama (2010).
The anti-insulin trimolecular complex in type 1 diabetes.
  Curr Opin Endocrinol Diabetes Obes, 17, 329-334.  
20872284 C.J.Kroger, R.R.Flores, M.Morillon, B.Wang, and R.Tisch (2010).
Dysregulation of thymic clonal deletion and the escape of autoreactive T cells.
  Arch Immunol Ther Exp (Warsz), 58, 449-457.  
20630474 G.I.van Boxel, S.Holmes, L.Fugger, and E.Y.Jones (2010).
An alternative conformation of the T-cell receptor alpha constant region.
  J Mol Biol, 400, 828-837.
PDB code: 3mff
20016505 H.von Boehmer, and F.Melchers (2010).
Checkpoints in lymphocyte development and autoimmune disease.
  Nat Immunol, 11, 14-20.  
  20856901 J.E.Slansky, and K.R.Jordan (2010).
The Goldilocks model for TCR-too much attraction might not be best for vaccine design.
  PLoS Biol, 8, 0.  
21115828 S.Günther, A.Schlundt, J.Sticht, Y.Roske, U.Heinemann, K.H.Wiesmüller, G.Jung, K.Falk, O.Rötzschke, and C.Freund (2010).
Bidirectional binding of invariant chain peptides to an MHC class II molecule.
  Proc Natl Acad Sci U S A, 107, 22219-22224.
PDB codes: 3pdo 3pgc 3pgd
19468823 Z.Spyranti, T.Tselios, G.Deraos, J.Matsoukas, and G.A.Spyroulias (2010).
NMR structural elucidation of myelin basic protein epitope 83-99 implicated in multiple sclerosis.
  Amino Acids, 38, 929-936.  
19714571 H.von Boehmer (2009).
Central tolerance: essential for preventing autoimmune disease?
  Eur J Immunol, 39, 2313-2316.  
19148199 K.C.Garcia, J.J.Adams, D.Feng, and L.K.Ely (2009).
The molecular basis of TCR germline bias for MHC is surprisingly simple.
  Nat Immunol, 10, 143-147.  
19699075 K.W.Wucherpfennig, M.J.Call, L.Deng, and R.Mariuzza (2009).
Structural alterations in peptide-MHC recognition by self-reactive T cell receptors.
  Curr Opin Immunol, 21, 590-595.  
19286348 L.Zhang, J.M.Jasinski, M.Kobayashi, B.Davenport, K.Johnson, H.Davidson, M.Nakayama, K.Haskins, and G.S.Eisenbarth (2009).
Analysis of T cell receptor beta chains that combine with dominant conserved TRAV5D-4*04 anti-insulin B:9-23 alpha chains.
  J Autoimmun, 33, 42-49.  
19303388 M.Harkiolaki, S.L.Holmes, P.Svendsen, J.W.Gregersen, L.T.Jensen, R.McMahon, M.A.Friese, G.van Boxel, R.Etzensperger, J.S.Tzartos, K.Kranc, S.Sainsbury, K.Harlos, E.D.Mellins, J.Palace, M.M.Esiri, P.A.van der Merwe, E.Y.Jones, and L.Fugger (2009).
T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides.
  Immunity, 30, 348-357.
PDB code: 2wbj
19472182 Y.Chen, Y.Shi, H.Cheng, Y.Q.An, and G.F.Gao (2009).
Structural immunology and crystallography help immunologists see the immune system in action: how T and NK cells touch their ligands.
  IUBMB Life, 61, 579-590.  
18763026 C.M.Costantino, C.Baecher-Allan, and D.A.Hafler (2008).
Multiple sclerosis and regulatory T cells.
  J Clin Immunol, 28, 697-706.  
18155234 C.McBeth, A.Seamons, J.C.Pizarro, S.J.Fleishman, D.Baker, T.Kortemme, J.M.Goverman, and R.K.Strong (2008).
A new twist in TCR diversity revealed by a forbidden alphabeta TCR.
  J Mol Biol, 375, 1306-1319.
PDB codes: 2p1y 2p24
18342005 D.I.Godfrey, J.Rossjohn, and J.McCluskey (2008).
The fidelity, occasional promiscuity, and versatility of T cell receptor recognition.
  Immunity, 28, 304-314.  
18207413 E.D.Mantzourani, K.Blokar, T.V.Tselios, J.M.Matsoukas, J.A.Platts, T.M.Mavromoustakos, and S.G.Grdadolnik (2008).
A combined NMR and molecular dynamics simulation study to determine the conformational properties of agonists and antagonists against experimental autoimmune encephalomyelitis.
  Bioorg Med Chem, 16, 2171-2182.  
18726714 E.J.Collins, and D.S.Riddle (2008).
TCR-MHC docking orientation: natural selection, or thymic selection?
  Immunol Res, 41, 267-294.  
  18713991 K.Kawamura, K.A.McLaughlin, R.Weissert, and T.G.Forsthuber (2008).
Myelin-reactive type B T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice.
  J Immunol, 181, 3202-3211.  
18157812 L.G.Petrich de Marquesini, A.K.Moustakas, I.J.Thomas, L.Wen, G.K.Papadopoulos, and F.S.Wong (2008).
Functional inhibition related to structure of a highly potent insulin-specific CD8 T cell clone using altered peptide ligands.
  Eur J Immunol, 38, 240-249.  
18678247 L.K.Ely, S.R.Burrows, A.W.Purcell, J.Rossjohn, and J.McCluskey (2008).
T-cells behaving badly: structural insights into alloreactivity and autoimmunity.
  Curr Opin Immunol, 20, 575-580.  
18304006 P.Marrack, J.P.Scott-Browne, S.Dai, L.Gapin, and J.W.Kappler (2008).
Evolutionarily conserved amino acids that control TCR-MHC interaction.
  Annu Rev Immunol, 26, 171-203.  
18456484 P.Marrack, K.Rubtsova, J.Scott-Browne, and J.W.Kappler (2008).
T cell receptor specificity for major histocompatibility complex proteins.
  Curr Opin Immunol, 20, 203-207.  
18513924 R.Etzensperger, R.M.McMahon, E.Y.Jones, and L.Fugger (2008).
Dissection of the multiple sclerosis associated DR2 haplotype.
  J Autoimmun, 31, 201-207.  
18703505 T.Mareeva, E.Martinez-Hackert, and Y.Sykulev (2008).
How a T cell receptor-like antibody recognizes major histocompatibility complex-bound peptide.
  J Biol Chem, 283, 29053-29059.
PDB codes: 3cvh 3cvi
18824684 Z.Kato, J.N.Stern, H.K.Nakamura, K.Kuwata, N.Kondo, and J.L.Strominger (2008).
Positioning of autoimmune TCR-Ob.2F3 and TCR-Ob.3D1 on the MBP85-99/HLA-DR2 complex.
  Proc Natl Acad Sci U S A, 105, 15523-15528.  
17559580 B.E.Hansen, A.H.Rasmussen, B.K.Jakobsen, L.P.Ryder, and A.Svejgaard (2007).
Extraordinary cross-reactivity of an autoimmune T-cell receptor recognizing specific peptides both on autologous and on allogeneic HLA class II molecules.
  Tissue Antigens, 70, 42-52.  
17268555 B.Moza, A.K.Varma, R.A.Buonpane, P.Zhu, C.A.Herfst, M.J.Nicholson, A.K.Wilbuer, N.P.Seth, K.W.Wucherpfennig, J.K.McCormick, D.M.Kranz, and E.J.Sundberg (2007).
Structural basis of T-cell specificity and activation by the bacterial superantigen TSST-1.
  EMBO J, 26, 1187-1197.
PDB code: 2ij0
17521918 C.Mazza, and B.Malissen (2007).
What guides MHC-restricted TCR recognition?
  Semin Immunol, 19, 225-235.  
17581593 D.B.Moody (2007).
Immunology: how a T cell sees sugar.
  Nature, 448, 36-37.  
17560120 E.J.Sundberg, L.Deng, and R.A.Mariuzza (2007).
TCR recognition of peptide/MHC class II complexes and superantigens.
  Semin Immunol, 19, 262-271.  
17917028 E.J.Yunis, J.Zuniga, V.Romero, and E.J.Yunis (2007).
Chimerism and tetragametic chimerism in humans: implications in autoimmunity, allorecognition and tolerance.
  Immunol Res, 38, 213-236.  
17304631 G.Cai, and D.A.Hafler (2007).
Multispecific responses by T cells expanded by endogenous self-peptide/MHC complexes.
  Eur J Immunol, 37, 602-612.  
17497145 G.P.Bondinas, A.K.Moustakas, and G.K.Papadopoulos (2007).
The spectrum of HLA-DQ and HLA-DR alleles, 2006: a listing correlating sequence and structure with function.
  Immunogenetics, 59, 539-553.  
  19662225 J.M.Kneller, T.Ehlen, J.P.Matisic, D.Miller, D.Van Niekerk, W.L.Lam, M.Marra, R.Richards-Kortum, M.Follen, C.Macaulay, and S.J.Jones (2007).
Using LongSAGE to Detect Biomarkers of Cervical Cancer Potentially Amenable to Optical Contrast Agent Labelling.
  Biomark Insights, 2, 447-461.  
17398114 K.W.Wucherpfennig, P.M.Allen, F.Celada, I.R.Cohen, R.De Boer, K.C.Garcia, B.Goldstein, R.Greenspan, D.Hafler, P.Hodgkin, E.S.Huseby, D.C.Krakauer, D.Nemazee, A.S.Perelson, C.Pinilla, R.K.Strong, and E.E.Sercarz (2007).
Polyspecificity of T cell and B cell receptor recognition.
  Semin Immunol, 19, 216-224.  
17418792 L.A.Colf, A.J.Bankovich, N.A.Hanick, N.A.Bowerman, L.L.Jones, D.M.Kranz, and K.C.Garcia (2007).
How a single T cell receptor recognizes both self and foreign MHC.
  Cell, 129, 135-146.
PDB codes: 2e7l 2oi9
17950605 L.Deng, and R.A.Mariuzza (2007).
Recognition of self-peptide-MHC complexes by autoimmune T-cell receptors.
  Trends Biochem Sci, 32, 500-508.  
17334368 L.Deng, R.J.Langley, P.H.Brown, G.Xu, L.Teng, Q.Wang, M.I.Gonzales, G.G.Callender, M.I.Nishimura, S.L.Topalian, and R.A.Mariuzza (2007).
Structural basis for the recognition of mutant self by a tumor-specific, MHC class II-restricted T cell receptor.
  Nat Immunol, 8, 398-408.
PDB codes: 2ial 2iam 2ian
18007679 N.J.Felix, and P.M.Allen (2007).
Specificity of T-cell alloreactivity.
  Nat Rev Immunol, 7, 942-953.  
16537438 A.A.Musse, J.M.Boggs, and G.Harauz (2006).
Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope.
  Proc Natl Acad Sci U S A, 103, 4422-4427.  
16925820 A.Lucchese, A.Mittelman, L.Tessitore, R.Serpico, A.A.Sinha, and D.Kanduc (2006).
Proteomic definition of a desmoglein linear determinant common to Pemphigus vulgaris and Pemphigus foliaceous.
  J Transl Med, 4, 37.  
16788072 B.Moza, R.A.Buonpane, P.Zhu, C.A.Herfst, A.K.Rahman, J.K.McCormick, D.M.Kranz, and E.J.Sundberg (2006).
Long-range cooperative binding effects in a T cell receptor variable domain.
  Proc Natl Acad Sci U S A, 103, 9867-9872.  
16420483 C.Farès, D.S.Libich, and G.Harauz (2006).
Solution NMR structure of an immunodominant epitope of myelin basic protein. Conformational dependence on environment of an intrinsically unstructured protein.
  FEBS J, 273, 601-614.  
16221670 C.Rückert, M.T.Fiorillo, B.Loll, R.Moretti, J.Biesiadka, W.Saenger, A.Ziegler, R.Sorrentino, and B.Uchanska-Ziegler (2006).
Conformational dimorphism of self-peptides and molecular mimicry in a disease-associated HLA-B27 subtype.
  J Biol Chem, 281, 2306-2316.
PDB code: 2a83
16557259 E.Y.Jones, L.Fugger, J.L.Strominger, and C.Siebold (2006).
MHC class II proteins and disease: a structural perspective.
  Nat Rev Immunol, 6, 271-282.  
16868084 I.Durinovic-Belló, S.Rosinger, J.A.Olson, M.Congia, R.C.Ahmad, M.Rickert, J.Hampl, H.Kalbacher, J.W.Drijfhout, E.D.Mellins, S.Al Dahouk, T.Kamradt, M.J.Maeurer, C.Nhan, B.O.Roep, B.O.Boehm, C.Polychronakos, G.T.Nepom, W.Karges, H.O.McDevitt, and G.Sønderstrup (2006).
DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype.
  Proc Natl Acad Sci U S A, 103, 11683-11688.  
16617112 L.K.Ely, T.Beddoe, C.S.Clements, J.M.Matthews, A.W.Purcell, L.Kjer-Nielsen, J.McCluskey, and J.Rossjohn (2006).
Disparate thermodynamics governing T cell receptor-MHC-I interactions implicate extrinsic factors in guiding MHC restriction.
  Proc Natl Acad Sci U S A, 103, 6641-6646.  
16551255 M.G.Rudolph, R.L.Stanfield, and I.A.Wilson (2006).
How TCRs bind MHCs, peptides, and coreceptors.
  Annu Rev Immunol, 24, 419-466.  
  16424227 M.Sospedra, P.A.Muraro, I.Stefanová, Y.Zhao, K.Chung, Y.Li, M.Giulianotti, R.Simon, R.Mariuzza, C.Pinilla, and R.Martin (2006).
Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype.
  J Immunol, 176, 1951-1961.  
17010587 M.Sospedra, and R.Martin (2006).
When T cells recognize a pattern, they might cause trouble.
  Curr Opin Immunol, 18, 697-703.  
16186824 F.E.Tynan, S.R.Burrows, A.M.Buckle, C.S.Clements, N.A.Borg, J.J.Miles, T.Beddoe, J.C.Whisstock, M.C.Wilce, S.L.Silins, J.M.Burrows, L.Kjer-Nielsen, L.Kostenko, A.W.Purcell, J.McCluskey, and J.Rossjohn (2005).
T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide.
  Nat Immunol, 6, 1114-1122.
PDB code: 2ak4
16260763 H.Li, S.Van Vranken, Y.Zhao, Z.Li, Y.Guo, L.Eisele, and Y.Li (2005).
Crystal structures of T cell receptor (beta) chains related to rheumatoid arthritis.
  Protein Sci, 14, 3025-3038.
PDB codes: 2axh 2axj
15843798 I.A.Wilson, and R.L.Stanfield (2005).
MHC restriction: slip-sliding away.
  Nat Immunol, 6, 434-435.  
16096054 K.C.Garcia, and E.J.Adams (2005).
How the T cell receptor sees antigen--a structural view.
  Cell, 122, 333-336.  
16079912 Y.Li, Y.Huang, J.Lue, J.A.Quandt, R.Martin, and R.A.Mariuzza (2005).
Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule.
  EMBO J, 24, 2968-2979.
PDB code: 1zgl
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.