PDBsum entry 1uvq

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protein ligands metals Protein-protein interface(s) links
Immunology PDB id
Protein chains
182 a.a. *
181 a.a. *
20 a.a. *
NAG ×2
Waters ×371
* Residue conservation analysis
PDB id:
Name: Immunology
Title: Crystal structure of hla-dq0602 in complex with a hypocretin peptide
Structure: Hla class ii histocompatibility antigen. Chain: a. Synonym: qa1 0602, Dq(5) alpha chain, dc-1 alpha chain. Engineered: yes. Hla class ii histocompatibility antigen. Chain: b. Synonym: dqb1 0602, Dqb1 0602 Beta chain, dq(5), dc-1. Engineered: yes. Orexin.
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: s2. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Expression_system_taxid: 7227
Biol. unit: Trimer (from PDB file)
1.8Å     R-factor:   0.189     R-free:   0.205
Authors: C.Siebold,B.E.Hansen,J.R.Wyer,K.Harlos,R.E.Esnouf, A.Svejgaard,J.I.Bell,J.L.Strominger,E.Y.Jones,L.Fugger
Key ref:
C.Siebold et al. (2004). Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy. Proc Natl Acad Sci U S A, 101, 1999-2004. PubMed id: 14769912 DOI: 10.1073/pnas.0308458100
22-Jan-04     Release date:   05-Feb-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P01909  (DQA1_HUMAN) -  HLA class II histocompatibility antigen, DQ alpha 1 chain
254 a.a.
182 a.a.*
Protein chain
Pfam   ArchSchema ?
P01920  (DQB1_HUMAN) -  HLA class II histocompatibility antigen, DQ beta 1 chain
261 a.a.
181 a.a.*
Protein chain
Pfam   ArchSchema ?
O43612  (OREX_HUMAN) -  Orexin
131 a.a.
20 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 48 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.0308458100 Proc Natl Acad Sci U S A 101:1999-2004 (2004)
PubMed id: 14769912  
Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy.
C.Siebold, B.E.Hansen, J.R.Wyer, K.Harlos, R.E.Esnouf, A.Svejgaard, J.I.Bell, J.L.Strominger, E.Y.Jones, L.Fugger.
The MHC class II molecule DQ0602 confers strong susceptibility to narcolepsy but dominant protection against type 1 diabetes. The crystal structure of DQ0602 reveals the molecular features underlying these contrasting genetic properties. Structural comparisons to homologous DQ molecules with differential disease associations highlight a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of an expanded peptide repertoire is critical for dominant protection against type 1 diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role.
  Selected figure(s)  
Figure 1.
Fig. 1. The crystal structure of DQ0602-hypocretin. (A) The solvent-accessible surface of the DQ0602 peptide binding groove is colored by electrostatic potential (blue, positive charge; red, negative charge) viewed onto the TCR recognition surface. The residues of the peptide are shown as ball-and-stick in atomic coloring (blue, nitrogen; red, oxygen; yellow, peptide carbon). The major pockets within the groove are labeled in the standard MHC class II nomenclature. (B) A composite omit map contoured at 1 is shown in blue chicken wire. The peptide is depicted in ball-and-stick colored as in A and viewed through the 1-helix. (C) A superposition of the peptides from the DQ0602-hypocretin and DQ0302-insulinB structures. The peptides are shown with atomic coloring as in A except for the insulinB peptide carbon atoms (green). The view is as in B, and the residues are labeled in the standard MHC class II nomenclature. (D) Superposition of the DQ0602 and DQ0302 peptide binding grooves. The C traces for DQ0602 (gray) and for DQ0302 (green) are viewed as in A. The well ordered residues of the hypocretin peptide and linker are shown with atomic coloring (peptide coloring as in A; orange, linker carbon). Residues 46 to 55 and 85 to 91 show significant main chain and side chain conformational changes between the two MHC class II structures. The C positions of these residues in DQ0602 are indicated by spheres (blue, -chain; magenta, -chain). The concerted conformational changes impact on the P1 pocket (see text) and on the heterodimer interface. In particular, residue 48 changes from leucine in DQ0302 to tryptophan in DQ0602, and the side chain of Trp-48 (shown in blue sticks) is reoriented to form a tight, hydrophobic interaction at the interface with the 2 domain.
Figure 3.
Fig. 3. The P6 pocket and T1D. (A) Stereoview of a superposition of selected residues from DQ0602-hypocretin with the equivalent residues from DQ0302-insulinB. Main chain is shown as coil, and selected residue side chains are depicted as ball-and-stick (yellow, hypocretin peptide; green, DQ0602; magenta, DQ0302-insulinB). The P6 residue in both the hypocretin and insulinB peptides is valine. (B) Stereoview of the DQ0602-hypocretin complex as in A. The volume bound by the blue chicken wire shows the increase in the P6 pocket size of DQ0602 when compared with DQ0302. The volume was defined by the program VOLUMES as local difference between the solvent-accessible surfaces of the two binding grooves after superposition.
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21299528 B.E.Hansen, C.H.Nielsen, H.O.Madsen, L.P.Ryder, B.K.Jakobsen, and A.Svejgaard (2011).
The HLA-DP2 protein binds the immunodominant epitope from myelin basic protein, MBP85-99, with high affinity.
  Tissue Antigens, 77, 229-234.  
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
21132285 F.Ling, L.Q.Wei, T.Wang, H.B.Wang, M.Zhuo, H.L.Du, J.F.Wang, and X.N.Wang (2011).
Characterization of the major histocompatibility complex class II DOB, DPB1, and DQB1 alleles in cynomolgus macaques of Vietnamese origin.
  Immunogenetics, 63, 155-166.  
21388362 M.C.Cho, S.Y.Ko, H.B.Oh, Y.S.Heo, and O.J.Kwon (2011).
HLA-DQB1*05:06, a novel HLA-DQB1*05 allele identified by sequence-based typing.
  Tissue Antigens, 77, 344-346.  
21133715 N.K.Akers, J.D.Curry, L.Conde, P.M.Bracci, M.T.Smith, and C.F.Skibola (2011).
Association of HLA-DQB1 alleles with risk of follicular lymphoma.
  Leuk Lymphoma, 52, 53-58.  
21134891 P.Benkert, M.Biasini, and T.Schwede (2011).
Toward the estimation of the absolute quality of individual protein structure models.
  Bioinformatics, 27, 343-350.  
20403960 A.Fontana, H.Gast, W.Reith, M.Recher, T.Birchler, and C.L.Bassetti (2010).
Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss?
  Brain, 133, 1300-1311.  
20221424 C.Brorsson, N.Tue Hansen, R.Bergholdt, S.Brunak, and F.Pociot (2010).
The type 1 diabetes - HLA susceptibility interactome--identification of HLA genotype-specific disease genes for type 1 diabetes.
  PLoS One, 5, e9576.  
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.  
18926972 B.Woelfing, A.Traulsen, M.Milinski, and T.Boehm (2009).
Does intra-individual major histocompatibility complex diversity keep a golden mean?
  Philos Trans R Soc Lond B Biol Sci, 364, 117-128.  
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.  
19017300 S.Caillat-Zucman (2009).
Molecular mechanisms of HLA association with autoimmune diseases.
  Tissue Antigens, 73, 1-8.  
19225081 S.Gaseitsiwe, D.Valentini, R.Ahmed, S.Mahdavifar, I.Magalhaes, J.Zerweck, M.Schutkowski, E.Gautherot, F.Montero, A.Ehrnst, M.Reilly, and M.Maeurer (2009).
Major histocompatibility complex class II molecule-human immunodeficiency virus peptide analysis using a microarray chip.
  Clin Vaccine Immunol, 16, 567-573.  
19416502 S.Justesen, M.Harndahl, K.Lamberth, L.L.Nielsen, and S.Buus (2009).
Functional recombinant MHC class II molecules and high-throughput peptide-binding assays.
  Immunome Res, 5, 2.  
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.  
18650831 E.L.Ivansson, J.J.Magnusson, P.K.Magnusson, H.A.Erlich, and U.B.Gyllensten (2008).
MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2.
  Genes Immun, 9, 613-623.  
18342260 E.Mignot (2008).
Excessive daytime sleepiness: population and etiology versus nosology.
  Sleep Med Rev, 12, 87-94.  
18427198 R.A.Hardie, M.Luo, B.Bruneau, E.Knight, N.J.Nagelkerke, J.Kimani, C.Wachihi, E.N.Ngugi, and F.A.Plummer (2008).
Human leukocyte antigen-DQ alleles and haplotypes and their associations with resistance and susceptibility to HIV-1 infection.
  AIDS, 22, 807-816.  
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.  
18291691 S.Overeem, J.L.Black, and G.J.Lammers (2008).
Narcolepsy: immunological aspects.
  Sleep Med Rev, 12, 95.  
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.  
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.  
17292770 Y.Dauvilliers, I.Arnulf, and E.Mignot (2007).
Narcolepsy with cataplexy.
  Lancet, 369, 499-511.  
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.  
16091932 I.K.Egorov (2006).
Mouse models of efficient and inefficient anti-tumor immunity, with emphasis on minimal residual disease and tumor escape.
  Cancer Immunol Immunother, 55, 1.  
  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.  
16409576 N.Miyamura, Y.Murata, K.Taketa, Y.Ichihara, T.Matsumura, H.Tokunaga, K.Matsumoto, M.Sakakida, and E.Araki (2006).
A case of insulin autoimmune syndrome with HLA DRB1*0404: impact on the hypothesis for the molecular pathogenesis involving DRB1 molecules.
  Diabet Med, 23, 104-105.  
15998789 N.N.Logunova, C.Viret, L.A.Pobezinsky, S.A.Miller, D.B.Kazansky, J.P.Sundberg, and A.V.Chervonsky (2005).
Restricted MHC-peptide repertoire predisposes to autoimmunity.
  J Exp Med, 202, 73-84.  
15573121 R.Horton, L.Wilming, V.Rand, R.C.Lovering, E.A.Bruford, V.K.Khodiyar, M.J.Lush, S.Povey, C.C.Talbot, M.W.Wright, H.M.Wain, J.Trowsdale, A.Ziegler, and S.Beck (2004).
Gene map of the extended human MHC.
  Nat Rev Genet, 5, 889-899.  
15469407 S.H.Shoshan, and A.Admon (2004).
MHC-bound antigens and proteomics for novel target discovery.
  Pharmacogenomics, 5, 845-859.  
15311276 S.Quaratino, E.Badami, Y.Y.Pang, I.Bartok, J.Dyson, D.Kioussis, M.Londei, and L.Maiuri (2004).
Degenerate self-reactive human T-cell receptor causes spontaneous autoimmune disease in mice.
  Nat Med, 10, 920-926.  
15331779 Z.Zavala-Ruiz, I.Strug, B.D.Walker, P.J.Norris, and L.J.Stern (2004).
A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition.
  Proc Natl Acad Sci U S A, 101, 13279-13284.
PDB codes: 1sje 1sjh
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.