RCSB PDB - 8VD0: Human TCR ET650-4 in complex with DQ8-InsC8-15-IAPP2

 8VD0

Human TCR ET650-4 in complex with DQ8-InsC8-15-IAPP2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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This is version 1.3 of the entry. See complete history


Literature

A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8.

Tran, M.T.Lim, J.J.Loh, T.J.Mannering, S.I.Rossjohn, J.Reid, H.H.

(2024) J Biol Chem 300: 107612-107612

  • DOI: https://doi.org/10.1016/j.jbc.2024.107612
  • Primary Citation of Related Structures:  
    8VCX, 8VCY, 8VD0, 8VD2, 8VDD, 8VDU

  • PubMed Abstract: 

    Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that has a strong HLA association, where a number of self-epitopes have been implicated in disease pathogenesis. Human pancreatic islet-infiltrating CD4 + T cell clones not only respond to proinsulin C-peptide (PI 40-54; GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI 40-47 -IAPP 74-80; GQVELGGG-NAVEVLK) presented by HLA-DQ8. How T cell receptors recognise self-peptide and cross-react to HIPs is unclear. We investigated the cross-reactivity of the CD4 + T cell clones reactive to native PI 40-54 epitope and multiple HIPs fused at the same N-terminus (PI 40-54 ) to the degradation products of two highly expressed pancreatic islet proteins, Neuropeptide Y (NPY 68-74 ) and amyloid polypeptide (IAPP 23-29 and IAPP 74-80 ). We observed that five out of the selected SKW3 T cell lines expressing TCRs isolated from CD4 + T cells of people with T1D responded to multiple HIPs. Despite shared TRAV26-1-TRBV5-1 gene usage in some T cells, these clones cross-reacted to varying degrees with the PI 40-54 and HIP epitopes. Crystal structures of two TRAV26-1 + -TRBV5-1 + T cell receptors (TCRs) in complex with PI 40-54 and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI 40-54 and HIP epitopes. Alanine scanning mutagenesis of the PI 40-54 and HIPs determined that the P2, P7 and P8 residues in these epitopes were key determinants of TCR specificity. Accordingly, we provide a molecular basis for cross-reactivity towards native insulin and HIP epitopes presented by HLA-DQ8.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
MHC class II HLA-DQ-alpha chainA,
C [auth F]
185Homo sapiensMutation(s): 1 
Gene Names: HLA-DQA1
UniProt
Find proteins for Q30069 (Homo sapiens)
Explore Q30069 
Go to UniProtKB:  Q30069
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ30069
Glycosylation
Glycosylation Sites: 2
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Hybrid insulin peptide (HIP; InsC8-15-IAPP74-80),MHC class II HLA-DQ-beta-1 chimeraB [auth C],
D [auth H]
213Homo sapiensMutation(s): 0 
UniProt
Find proteins for O19707 (Homo sapiens)
Explore O19707 
Go to UniProtKB:  O19707
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO19707
Glycosylation
Glycosylation Sites: 1
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
T-CELL-RECEPTOR, TCR ET650-4 alphaE [auth D],
G [auth I]
206Homo sapiensMutation(s): 0 
Gene Names: TRAV26-1*01
Entity Groups  
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Sequence Annotations
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
T-CELL-RECEPTOR, TCR ET650-4 betaF [auth E],
H [auth J]
240Homo sapiensMutation(s): 0 
Gene Names: TRBV5-1*01
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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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 
I [auth A],
J [auth A],
O [auth F],
P [auth F],
T [auth H]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
BA [auth I]
EA [auth J]
M [auth A]
N [auth C]
W [auth D]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
GOL
Query on GOL

Download Ideal Coordinates CCD File 
AA [auth I]
CA [auth J]
DA [auth J]
K [auth A]
L [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.220 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.193α = 90
b = 139.303β = 93.698
c = 120.495γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
autoXDSdata reduction
Cootmodel building
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted NAGClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Health and Medical Research Council (NHMRC, Australia)Australia2008981
National Health and Medical Research Council (NHMRC, Australia)AustraliaAPP1123586

Revision History  (Full details and data files)

  • Version 1.0: 2024-08-07
    Type: Initial release
  • Version 1.1: 2024-08-14
    Changes: Database references
  • Version 1.2: 2024-09-04
    Changes: Database references
  • Version 1.3: 2024-10-30
    Changes: Structure summary