5JZI

Crystal structure of 1406 TCR bound to HLA-A2 with HCV 1406-1415 antigen peptide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

How an alloreactive T-cell receptor achieves peptide and MHC specificity.

Wang, Y.Singh, N.K.Spear, T.T.Hellman, L.M.Piepenbrink, K.H.McMahan, R.H.Rosen, H.R.Vander Kooi, C.W.Nishimura, M.I.Baker, B.M.

(2017) Proc Natl Acad Sci U S A 114: E4792-E4801

  • DOI: https://doi.org/10.1073/pnas.1700459114
  • Primary Citation of Related Structures:  
    5JZI

  • PubMed Abstract: 

    T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus-host disease. Here, we show how an alloreactive TCR achieves peptide and MHC specificity. The HCV1406 TCR was cloned from T cells that expanded when a hepatitis C virus (HCV)-infected HLA-A2 - individual received an HLA-A2 + liver allograft. HCV1406 was subsequently shown to recognize the HCV nonstructural protein 3 (NS3):1406-1415 epitope with high specificity when presented by HLA-A2. We show that NS3/HLA-A2 recognition by the HCV1406 TCR is critically dependent on features unique to both the allo-MHC and the NS3 epitope. We also find cooperativity between structural mimicry and a crucial peptide "hot spot" and demonstrate its role, along with the MHC, in directing the specificity of allorecognition. Our results help explain the paradox of specificity in alloreactive TCRs and have implications for their use in immunotherapy and related efforts to manipulate TCR recognition, as well as alloreactivity in general.


  • Organizational Affiliation

    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HLA class I histocompatibility antigen, A-2 alpha chainA,
D [auth F]
275Homo sapiensMutation(s): 0 
Gene Names: HLA-AHLAA
UniProt & NIH Common Fund Data Resources
Find proteins for P04439 (Homo sapiens)
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Go to UniProtKB:  P04439
PHAROS:  P04439
GTEx:  ENSG00000206503 
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UniProt GroupP04439
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-2-microglobulinB,
E [auth G]
100Homo sapiensMutation(s): 0 
Gene Names: B2MCDABP0092HDCMA22P
UniProt & NIH Common Fund Data Resources
Find proteins for P61769 (Homo sapiens)
Explore P61769 
Go to UniProtKB:  P61769
PHAROS:  P61769
GTEx:  ENSG00000166710 
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UniProt GroupP61769
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
KLV peptideC,
F [auth H]
10Hepacivirus hominisMutation(s): 0 
UniProt
Find proteins for P27958 (Hepatitis C virus genotype 1a (isolate H77))
Explore P27958 
Go to UniProtKB:  P27958
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UniProt GroupP27958
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
HCV1406 TCR alpha chainG [auth D],
I
211Homo sapiensMutation(s): 0 
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
HCV1406 TCR beta chainH [auth E],
J
245Homo sapiensMutation(s): 0 
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.201 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 128.76α = 90
b = 128.76β = 90
c = 223.59γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata scaling
PHENIXphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-31
    Type: Initial release
  • Version 1.1: 2017-06-28
    Changes: Database references
  • Version 1.2: 2019-07-31
    Changes: Data collection, Derived calculations
  • Version 1.3: 2020-06-24
    Changes: Advisory
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Refinement description