6V1A

immune receptor complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 

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Ligand Structure Quality Assessment 


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Literature

The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR.

Lim, J.J.Jones, C.M.Loh, T.J.Ting, Y.T.Zareie, P.Loh, K.L.Felix, N.J.Suri, A.McKinnon, M.Stevenaert, F.Sharma, R.K.Klareskog, L.Malmstrom, V.Baker, D.G.Purcell, A.W.Reid, H.H.La Gruta, N.L.Rossjohn, J.

(2021) Sci Immunol 6

  • DOI: https://doi.org/10.1126/sciimmunol.abe0896
  • Primary Citation of Related Structures:  
    6V0Y, 6V13, 6V15, 6V18, 6V19, 6V1A

  • PubMed Abstract: 

    Individuals expressing HLA-DR4 bearing the shared susceptibility epitope (SE) have an increased risk of developing rheumatoid arthritis (RA). Posttranslational modification of self-proteins via citrullination leads to the formation of neoantigens that can be presented by HLA-DR4 SE allomorphs. However, in T cell-mediated autoimmunity, the interplay between the HLA molecule, posttranslationally modified epitope(s), and the responding T cell repertoire remains unclear. In HLA-DR4 transgenic mice, we show that immunization with a Fibβ-74cit 69-81 peptide led to a population of HLA-DR4 Fibβ-74cit69-81 tetramer + T cells that exhibited biased T cell receptor (TCR) β chain usage, which was attributable to selective clonal expansion from the preimmune repertoire. Crystal structures of pre- and postimmune TCRs showed that the SE of HLA-DR4 represented a main TCR contact zone. Immunization with a double citrullinated epitope (Fibβ-72,74cit 69-81 ) altered the responding HLA-DR4 tetramer + T cell repertoire, which was due to the P2-citrulline residue interacting with the TCR itself. We show that the SE of HLA-DR4 has dual functionality, namely, presentation and a direct TCR recognition determinant. Analogous biased TCR β chain usage toward the Fibβ-74cit 69-81 peptide was observed in healthy HLA-DR4 + individuals and patients with HLA-DR4 + RA, thereby suggesting a link to human RA.


  • Organizational Affiliation

    Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HLA class II histocompatibility antigen, DR alpha chain189Homo sapiensMutation(s): 0 
Gene Names: HLA-DRAHLA-DRA1
UniProt & NIH Common Fund Data Resources
Find proteins for P01903 (Homo sapiens)
Explore P01903 
Go to UniProtKB:  P01903
PHAROS:  P01903
GTEx:  ENSG00000204287 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01903
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
HLA class II histocompatibility antigen, DRB1-4 beta chain198Homo sapiensMutation(s): 0 
Gene Names: HLA-DRB1
UniProt & NIH Common Fund Data Resources
Find proteins for P01911 (Homo sapiens)
Explore P01911 
Go to UniProtKB:  P01911
PHAROS:  P01911
GTEx:  ENSG00000196126 
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UniProt GroupP01911
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Fibrinogen beta 74cit69-8113Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P02675 (Homo sapiens)
Explore P02675 
Go to UniProtKB:  P02675
PHAROS:  P02675
GTEx:  ENSG00000171564 
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UniProt GroupP02675
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
M134 TCR alpha chain209Mus musculusMutation(s): 0 
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
M134 TCR beta chain242Mus musculusMutation(s): 0 
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Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
H [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
AA [auth E]
BA [auth E]
CA [auth E]
I [auth B]
J [auth B]
AA [auth E],
BA [auth E],
CA [auth E],
I [auth B],
J [auth B],
K [auth B],
L [auth B],
M [auth C],
O [auth D],
P [auth D],
Q [auth D],
R [auth D],
S [auth D],
T [auth D],
U [auth D],
V [auth D],
W [auth D],
X [auth E],
Y [auth E],
Z [auth E]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
N [auth D]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CIR
Query on CIR
C
L-PEPTIDE LINKINGC6 H13 N3 O3ARG
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.188 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 149.344α = 90
b = 56.99β = 90.87
c = 131.184γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Australian Research Council (ARC)AustraliaCE140100011

Revision History  (Full details and data files)

  • Version 1.0: 2020-11-25
    Type: Initial release
  • Version 1.1: 2021-06-09
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Derived calculations