spacer
spacer

PDBsum entry 1s9v

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Immune system PDB id
1s9v
Jmol
Contents
Protein chains
179 a.a. *
181 a.a. *
11 a.a. *
Ligands
EDO ×4
Waters ×354
* Residue conservation analysis
PDB id:
1s9v
Name: Immune system
Title: Crystal structure of hla-dq2 complexed with deamidated gliadin peptide
Structure: Hla class ii histocompatibility antigen, dq(3) alpha chain. Chain: a, d. Fragment: residues (-1)-191. Synonym: hla-dq2 alpha chain, hla-dqa1 0501, Dc-alpha, hla- dca. Engineered: yes. Hla class ii histocompatibility antigen, dq(1) beta chain.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Synthetic: yes. Other_details: chemically synthesized
Biol. unit: Trimer (from PQS)
Resolution:
2.22Å     R-factor:   0.221     R-free:   0.283
Authors: C.-Y.Kim,H.Quarsten,E.Bergseng,C.Khosla,L.M.Sollid
Key ref:
C.Y.Kim et al. (2004). Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci U S A, 101, 4175-4179. PubMed id: 15020763 DOI: 10.1073/pnas.0306885101
Date:
05-Feb-04     Release date:   02-Mar-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01909  (DQA1_HUMAN) -  HLA class II histocompatibility antigen, DQ alpha 1 chain
Seq:
Struc:
254 a.a.
179 a.a.
Protein chains
Pfam   ArchSchema ?
P01920  (DQB1_HUMAN) -  HLA class II histocompatibility antigen, DQ beta 1 chain
Seq:
Struc:
261 a.a.
181 a.a.*
Protein chains
No UniProt id for this chain
Struc: 11 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 21 residue positions (black crosses)

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

 

 
DOI no: 10.1073/pnas.0306885101 Proc Natl Acad Sci U S A 101:4175-4179 (2004)
PubMed id: 15020763  
 
 
Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease.
C.Y.Kim, H.Quarsten, E.Bergseng, C.Khosla, L.M.Sollid.
 
  ABSTRACT  
 
Celiac disease, also known as celiac sprue, is a gluten-induced autoimmune-like disorder of the small intestine, which is strongly associated with HLA-DQ2. The structure of DQ2 complexed with an immunogenic epitope from gluten, QLQPFPQPELPY, has been determined to 2.2-A resolution by x-ray crystallography. The glutamate at P6, which is formed by tissue transglutaminase-catalyzed deamidation, is an important anchor residue as it participates in an extensive hydrogen-bonding network involving Lys-beta71 of DQ2. The gluten peptide-DQ2 complex retains critical hydrogen bonds between the MHC and the peptide backbone despite the presence of many proline residues in the peptide that are unable to participate in amide-mediated hydrogen bonds. Positioning of proline residues such that they do not interfere with backbone hydrogen bonding results in a reduction in the number of registers available for gluten peptides to bind to MHC class II molecules and presumably impairs the likelihood of establishing favorable side-chain interactions. The HLA association in celiac disease can be explained by a superior ability of DQ2 to bind the biased repertoire of proline-rich gluten peptides that have survived gastrointestinal digestion and that have been deamidated by tissue transglutaminase. Finally, surface-exposed proline residues in the proteolytically resistant ligand were replaced with functionalized analogs, thereby providing a starting point for the design of orally active agents for blocking gluten-induced toxicity.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Hydrogen-bonding network in the epitope-binding site of DQ2. I-gliadin is shown in yellow (C, yellow; N, blue; O, red), and HLA-DQ2 - and -chains are shown in gray (C, gray; N, blue; O, red). Gray spheres represent water molecules. Atom-to-atom distances are given in Å.
Figure 3.
Fig. 3. (A) Binding of a peptide that does not contain any Pro residues to HLA-DQ2. A number of peptide main-chain NH groups form hydrogen bonds in the peptide binding site. Several peptide side-chains dock into binding pockets (P1, P4, P6, P7, P9) of the HLA molecule, providing additional binding energy and serving as a selectivity filter. (B) Binding of a Pro-rich peptide (such as the I-gliadin) to HLA-DQ2 in a favorable register. Hydrogen-bond interactions involving peptide main-chain NH groups are still established, although there is significantly less main-chain NH groups available. (C) The same peptide in a shifted register cannot form such hydrogen bonds. Similarly, peptides that have Pro at unfavorable locations cannot form such hydrogen bonds, thereby limiting the registers available for binding.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21350675 A.Martin, G.De Vivo, and V.Gentile (2011).
Possible role of the transglutaminases in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases.
  Int J Alzheimers Dis, 2011, 865432.  
20736999 J.Huan, R.Meza-Romero, J.L.Mooney, A.A.Vandenbark, H.Offner, and G.G.Burrows (2011).
Single-chain recombinant HLA-DQ2.5/peptide molecules block α2-gliadin-specific pathogenic CD4+ T-cell proliferation and attenuate production of inflammatory cytokines: a potential therapy for celiac disease.
  Mucosal Immunol, 4, 112-120.  
21294744 P.Fric, D.Gabrovska, and J.Nevoral (2011).
Celiac disease, gluten-free diet, and oats.
  Nutr Rev, 69, 107-115.  
21278765 T.Matthias, S.Neidhöfer, S.Pfeiffer, K.Prager, S.Reuter, and M.E.Gershwin (2011).
Novel trends in celiac disease.
  Cell Mol Immunol, 8, 121-125.  
21219178 V.Abadie, L.M.Sollid, L.B.Barreiro, and B.Jabri (2011).
Integration of genetic and immunological insights into a model of celiac disease pathogenesis.
  Annu Rev Immunol, 29, 493-525.  
20419103 K.Mazumdar, X.Alvarez, J.T.Borda, J.Dufour, E.Martin, M.T.Bethune, C.Khosla, and K.Sestak (2010).
Visualization of transepithelial passage of the immunogenic 33-residue peptide from alpha-2 gliadin in gluten-sensitive macaques.
  PLoS One, 5, e10228.  
20122230 K.Yeturu, T.Utriainen, G.J.Kemp, and N.Chandra (2010).
An automated framework for understanding structural variations in the binding grooves of MHC class II molecules.
  BMC Bioinformatics, 11, S55.  
20446081 M.M.da Silva Neves, M.B.González-Garcia, H.P.Nouws, C.Delerue-Matos, A.Santos-Silva, and A.Costa-García (2010).
Celiac disease diagnosis and gluten-free food analytical control.
  Anal Bioanal Chem, 397, 1743-1753.  
20877349 M.Pinier, G.Fuhrmann, E.Verdu, and J.C.Leroux (2010).
Prevention measures and exploratory pharmacological treatments of celiac disease.
  Am J Gastroenterol, 105, 2551.  
20190752 P.C.Dubois, G.Trynka, L.Franke, K.A.Hunt, J.Romanos, A.Curtotti, A.Zhernakova, G.A.Heap, R.Adány, A.Aromaa, M.T.Bardella, L.H.van den Berg, N.A.Bockett, E.G.de la Concha, B.Dema, R.S.Fehrmann, M.Fernández-Arquero, S.Fiatal, E.Grandone, P.M.Green, H.J.Groen, R.Gwilliam, R.H.Houwen, S.E.Hunt, K.Kaukinen, D.Kelleher, I.Korponay-Szabo, K.Kurppa, P.MacMathuna, M.Mäki, M.C.Mazzilli, O.T.McCann, M.L.Mearin, C.A.Mein, M.M.Mirza, V.Mistry, B.Mora, K.I.Morley, C.J.Mulder, J.A.Murray, C.Núñez, E.Oosterom, R.A.Ophoff, I.Polanco, L.Peltonen, M.Platteel, A.Rybak, V.Salomaa, J.J.Schweizer, M.P.Sperandeo, G.J.Tack, G.Turner, J.H.Veldink, W.H.Verbeek, R.K.Weersma, V.M.Wolters, E.Urcelay, B.Cukrowska, L.Greco, S.L.Neuhausen, R.McManus, D.Barisani, P.Deloukas, J.C.Barrett, P.Saavalainen, C.Wijmenga, and D.A.van Heel (2010).
Multiple common variants for celiac disease influencing immune gene expression.
  Nat Genet, 42, 295-302.  
20632103 V.De Re, M.P.Simula, V.Canzonieri, and R.Cannizzaro (2010).
Proteomic analyses lead to a better understanding of celiac disease: focus on epitope recognition and autoantibodies.
  Dig Dis Sci, 55, 3041-3046.  
19394538 A.Di Sabatino, and G.R.Corazza (2009).
Coeliac disease.
  Lancet, 373, 1480-1493.  
19935805 B.Jabri, and L.M.Sollid (2009).
Tissue-mediated control of immunopathology in coeliac disease.
  Nat Rev Immunol, 9, 858-870.  
19079330 B.Meresse, J.Ripoche, M.Heyman, and N.Cerf-Bensussan (2009).
Celiac disease: from oral tolerance to intestinal inflammation, autoimmunity and lymphomagenesis.
  Mucosal Immunol, 2, 8.  
19718029 L.E.Fallang, E.Bergseng, K.Hotta, A.Berg-Larsen, C.Y.Kim, and L.M.Sollid (2009).
Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation.
  Nat Immunol, 10, 1096-1101.  
19538316 M.Heyman, and S.Menard (2009).
Pathways of gliadin transport in celiac disease.
  Ann N Y Acad Sci, 1165, 274-278.  
19500688 M.M.Pietzak, T.C.Schofield, M.J.McGinniss, and R.M.Nakamura (2009).
Stratifying risk for celiac disease in a large at-risk United States population by using HLA alleles.
  Clin Gastroenterol Hepatol, 7, 966-971.  
19017300 S.Caillat-Zucman (2009).
Molecular mechanisms of HLA association with autoimmune diseases.
  Tissue Antigens, 73, 1-8.  
18987854 U.Jüse, B.Fleckenstein, E.Bergseng, and L.M.Sollid (2009).
Soluble HLA-DQ2 expressed in S2 cells copurifies with a high affinity insect cell derived protein.
  Immunogenetics, 61, 81-89.  
18854049 C.S.Parry, and B.R.Brooks (2008).
A new model defines the minimal set of polymorphism in HLA-DQ and -DR that determines susceptibility and resistance to autoimmune diabetes.
  Biol Direct, 3, 42.  
18076355 F.Megiorni, B.Mora, M.Bonamico, R.Nenna, M.Di Pierro, C.Catassi, S.Drago, and M.C.Mazzilli (2008).
A rapid and sensitive method to detect specific human lymphocyte antigen (HLA) class II alleles associated with celiac disease.
  Clin Chem Lab Med, 46, 193-196.  
18799120 J.Tye-Din, and R.Anderson (2008).
Immunopathogenesis of celiac disease.
  Curr Gastroenterol Rep, 10, 458-465.  
18425213 M.T.Bethune, and C.Khosla (2008).
Parallels between pathogens and gluten peptides in celiac sprue.
  PLoS Pathog, 4, e34.  
18365012 M.T.Bethune, E.Ribka, C.Khosla, and K.Sestak (2008).
Transepithelial transport and enzymatic detoxification of gluten in gluten-sensitive rhesus macaques.
  PLoS ONE, 3, e1857.  
18713140 P.C.Dubois, and D.A.van Heel (2008).
Translational mini-review series on the immunogenetics of gut disease: immunogenetics of coeliac disease.
  Clin Exp Immunol, 153, 162-173.  
18166587 T.Matysiak-Budnik, I.C.Moura, M.Arcos-Fajardo, C.Lebreton, S.Ménard, C.Candalh, K.Ben-Khalifa, C.Dugave, H.Tamouza, G.van Niel, Y.Bouhnik, D.Lamarque, S.Chaussade, G.Malamut, C.Cellier, N.Cerf-Bensussan, R.C.Monteiro, and M.Heyman (2008).
Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease.
  J Exp Med, 205, 143-154.  
17513580 C.G.Rizzello, M.De Angelis, R.Di Cagno, A.Camarca, M.Silano, I.Losito, M.De Vincenzi, M.D.De Bari, F.Palmisano, F.Maurano, C.Gianfrani, and M.Gobbetti (2007).
Highly efficient gluten degradation by lactobacilli and fungal proteases during food processing: new perspectives for celiac disease.
  Appl Environ Microbiol, 73, 4499-4507.  
17678925 C.Gianfrani, R.A.Siciliano, A.M.Facchiano, A.Camarca, M.F.Mazzeo, S.Costantini, V.M.Salvati, F.Maurano, G.Mazzarella, G.Iaquinto, P.Bergamo, and M.Rossi (2007).
Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease.
  Gastroenterology, 133, 780-789.  
17592366 D.Detel, M.Persić, and J.Varljen (2007).
Serum and intestinal dipeptidyl peptidase IV (DPP IV/CD26) activity in children with celiac disease.
  J Pediatr Gastroenterol Nutr, 45, 65-70.  
17854603 D.Schuppan, and Y.Junker (2007).
Turning swords into plowshares: transglutaminase to detoxify gluten.
  Gastroenterology, 133, 1025-1028.  
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.  
17484880 J.Mallegol, G.Van Niel, C.Lebreton, Y.Lepelletier, C.Candalh, C.Dugave, J.K.Heath, G.Raposo, N.Cerf-Bensussan, and M.Heyman (2007).
T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells.
  Gastroenterology, 132, 1866-1876.  
17681795 J.Xia, E.Bergseng, B.Fleckenstein, M.Siegel, C.Y.Kim, C.Khosla, and L.M.Sollid (2007).
Cyclic and dimeric gluten peptide analogues inhibiting DQ2-mediated antigen presentation in celiac disease.
  Bioorg Med Chem, 15, 6565-6573.  
  18084083 K.N.Henderson, H.H.Reid, N.A.Borg, S.E.Broughton, T.Huyton, R.P.Anderson, J.McCluskey, and J.Rossjohn (2007).
The production and crystallization of the human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliac disease.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 1021-1025.  
17629515 K.N.Henderson, J.A.Tye-Din, H.H.Reid, Z.Chen, N.A.Borg, T.Beissbarth, A.Tatham, S.I.Mannering, A.W.Purcell, N.L.Dudek, D.A.van Heel, J.McCluskey, J.Rossjohn, and R.P.Anderson (2007).
A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease.
  Immunity, 27, 23-34.
PDB code: 2nna
17324400 M.Benahmed, B.Meresse, B.Arnulf, U.Barbe, J.J.Mention, V.Verkarre, M.Allez, C.Cellier, O.Hermine, and N.Cerf-Bensussan (2007).
Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease.
  Gastroenterology, 132, 994.  
17200705 M.F.Kagnoff (2007).
Celiac disease: pathogenesis of a model immunogenetic disease.
  J Clin Invest, 117, 41-49.  
17383437 M.F.Kagnoff (2007).
Mucosal inflammation in celiac disease: interleukin-15 meets transforming growth factor beta-1.
  Gastroenterology, 132, 1174-1176.  
17631122 M.F.Kagnoff (2007).
2007 William K. Warren, Jr., prize for excellence in celiac disease research awarded to professor Ludvig M. Sollid of Oslo, Norway.
  Gastroenterology, 133, 9.  
17590341 M.Siegel, J.Xia, and C.Khosla (2007).
Structure-based design of alpha-amido aldehyde containing gluten peptide analogues as modulators of HLA-DQ2 and transglutaminase 2.
  Bioorg Med Chem, 15, 6253-6261.  
17207708 R.J.Duquesnoy, and M.Askar (2007).
HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. V. Eplet matching for HLA-DR, HLA-DQ, and HLA-DP.
  Hum Immunol, 68, 12-25.  
17059521 A.Kapitány, L.Tóth, J.Tumpek, I.Csípo, E.Sipos, N.Woolley, J.Partanen, G.Szegedi, E.Oláh, S.Sipka, and I.R.Korponay-Szabó (2006).
Diagnostic significance of HLA-DQ typing in patients with previous coeliac disease diagnosis based on histology alone.
  Aliment Pharmacol Ther, 24, 1395-1402.  
16753344 A.Spurkland, and L.M.Sollid (2006).
Mapping genes and pathways in autoimmune disease.
  Trends Immunol, 27, 336-342.  
16951668 B.Jabri, and L.M.Sollid (2006).
Mechanisms of disease: immunopathogenesis of celiac disease.
  Nat Clin Pract Gastroenterol Hepatol, 3, 516-525.  
16766754 D.A.van Heel, and J.West (2006).
Recent advances in coeliac disease.
  Gut, 55, 1037-1046.  
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.  
16464085 J.Xia, M.Siegel, E.Bergseng, L.M.Sollid, and C.Khosla (2006).
Inhibition of HLA-DQ2-mediated antigen presentation by analogues of a high affinity 33-residue peptide from alpha2-gliadin.
  J Am Chem Soc, 128, 1859-1867.  
16409146 P.H.Green, and B.Jabri (2006).
Celiac disease.
  Annu Rev Med, 57, 207-221.  
16299041 R.P.Anderson, D.A.van Heel, J.A.Tye-Din, D.P.Jewell, and A.V.Hill (2006).
Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease.
  Gut, 55, 485-491.  
16878175 S.Tollefsen, H.Arentz-Hansen, B.Fleckenstein, O.Molberg, M.Ráki, W.W.Kwok, G.Jung, K.E.Lundin, and L.M.Sollid (2006).
HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease.
  J Clin Invest, 116, 2226-2236.  
16343885 V.H.Engelhard, M.Altrich-Vanlith, M.Ostankovitch, and A.L.Zarling (2006).
Post-translational modifications of naturally processed MHC-binding epitopes.
  Curr Opin Immunol, 18, 92-97.  
16530013 ..Molberg, and L.M.Sollid (2006).
A gut feeling for joint inflammation - using coeliac disease to understand rheumatoid arthritis.
  Trends Immunol, 27, 188-194.  
16048552 B.Jabri, D.D.Kasarda, and P.H.Green (2005).
Innate and adaptive immunity: the yin and yang of celiac disease.
  Immunol Rev, 206, 219-231.  
15714306 D.Stepniak, L.W.Vader, Y.Kooy, P.A.van Veelen, A.Moustakas, N.A.Papandreou, E.Eliopoulos, J.W.Drijfhout, G.K.Papadopoulos, and F.Koning (2005).
T-cell recognition of HLA-DQ2-bound gluten peptides can be influenced by an N-terminal proline at p-1.
  Immunogenetics, 57, 8.  
16091925 F.Koning, L.Gilissen, and C.Wijmenga (2005).
Gluten: a two-edged sword. Immunopathogenesis of celiac disease.
  Springer Semin Immunopathol, 27, 217-232.  
16230082 F.Koning (2005).
Celiac disease: caught between a rock and a hard place.
  Gastroenterology, 129, 1294-1301.  
15711206 G.Robins, and P.D.Howdle (2005).
Advances in celiac disease.
  Curr Opin Gastroenterol, 21, 152-161.  
16265155 L.M.Sollid, and C.Khosla (2005).
Future therapeutic options for celiac disease.
  Nat Clin Pract Gastroenterol Hepatol, 2, 140-147.  
16285941 L.Maiuri, C.Ciacci, I.Ricciardelli, L.Vacca, V.Raia, A.Rispo, M.Griffin, T.Issekutz, S.Quaratino, and M.Londei (2005).
Unexpected role of surface transglutaminase type II in celiac disease.
  Gastroenterology, 129, 1400-1413.  
16212427 L.Shan, S.W.Qiao, H.Arentz-Hansen, ..Molberg, G.M.Gray, L.M.Sollid, and C.Khosla (2005).
Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue.
  J Proteome Res, 4, 1732-1741.  
15825116 M.F.Kagnoff (2005).
Overview and pathogenesis of celiac disease.
  Gastroenterology, 128, S10-S18.  
16296811 S.Venkatesh, M.E.Byrne, N.A.Peppas, and J.Z.Hilt (2005).
Applications of biomimetic systems in drug delivery.
  Expert Opin Drug Deliv, 2, 1085-1096.  
16143118 T.Matysiak-Budnik, C.Candalh, C.Cellier, C.Dugave, A.Namane, T.Vidal-Martinez, N.Cerf-Bensussan, and M.Heyman (2005).
Limited efficiency of prolyl-endopeptidase in the detoxification of gliadin peptides in celiac disease.
  Gastroenterology, 129, 786-796.  
15526039 H.Arentz-Hansen, B.Fleckenstein, ..Molberg, H.Scott, F.Koning, G.Jung, P.Roepstorff, K.E.Lundin, and L.M.Sollid (2004).
The molecular basis for oat intolerance in patients with celiac disease.
  PLoS Med, 1, e1.  
15367850 W.R.Treem (2004).
Emerging concepts in celiac disease.
  Curr Opin Pediatr, 16, 552-559.  
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.