6PZ5

Crystal Structure of HLA-B*2703 in complex with LRN, a self-peptide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Allelic association with ankylosing spondylitis fails to correlate with human leukocyte antigen B27 homodimer formation.

Lim Kam Sian, T.C.C.Indumathy, S.Halim, H.Greule, A.Cryle, M.J.Bowness, P.Rossjohn, J.Gras, S.Purcell, A.W.Schittenhelm, R.B.

(2019) J Biol Chem 294: 20185-20195

  • DOI: https://doi.org/10.1074/jbc.RA119.010257
  • Primary Citation of Related Structures:  
    6PYJ, 6PYL, 6PYV, 6PYW, 6PZ5

  • PubMed Abstract: 

    Expression of human leukocyte antigen (HLA)-B27 is strongly associated with predisposition toward ankylosing spondylitis (AS) and other spondyloarthropathies. However, the exact involvement of HLA-B27 in disease initiation and progression remains unclear. The homodimer theory, which proposes that HLA-B27 heavy chains aberrantly form homodimers, is a central hypothesis that attempts to explain the role of HLA-B27 in disease pathogenesis. Here, we examined the ability of the eight most prevalent HLA-B27 allotypes (HLA-B*27:02 to HLA-B*27:09) to form homodimers. We observed that HLA-B*27:03, a disease-associated HLA-B27 subtype, showed a significantly reduced ability to form homodimers compared with all other allotypes, including the non-disease-associated/protective allotypes HLA-B*27:06 and HLA-B*27:09. We used X-ray crystallography and site-directed mutagenesis to unravel the molecular and structural mechanisms in HLA-B*27:03 that are responsible for its compromised ability to form homodimers. We show that polymorphism at position 59, which differentiates HLA-B*27:03 from all other allotypes, is responsible for its compromised ability to form homodimers. Indeed, histidine 59 in HLA-B*27:03 leads to a series of local conformational changes that act in concert to reduce the accessibility of the nearby cysteine 67, an essential amino acid residue for the formation of HLA-B27 homodimers. Considered together, the ability of both protective and disease-associated HLA-B27 allotypes to form homodimers and the failure of HLA-B*27:03 to form homodimers challenge the role of HLA-B27 homodimers in AS pathoetiology. Rather, this work implicates other features, such as peptide binding and antigen presentation, as pivotal mechanisms for disease pathogenesis.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HLA class I histocompatibility antigen, B*27:03 alpha chain276Homo sapiensMutation(s): 1 
Gene Names: HLA-BHLAB
UniProt & NIH Common Fund Data Resources
Find proteins for P01889 (Homo sapiens)
Explore P01889 
Go to UniProtKB:  P01889
PHAROS:  P01889
GTEx:  ENSG00000234745 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01889
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-2-microglobulin99Homo 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 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP61769
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
LRN peptide9Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P37268 (Homo sapiens)
Explore P37268 
Go to UniProtKB:  P37268
PHAROS:  P37268
GTEx:  ENSG00000079459 
Entity Groups  
UniProt GroupP37268
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.53 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.052α = 90
b = 82.51β = 90
c = 109.625γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHASERphasing
BUSTERrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2019-11-27 
  • Deposition Author(s): Gras, S.

Revision History  (Full details and data files)

  • Version 1.0: 2019-11-27
    Type: Initial release
  • Version 1.1: 2019-12-04
    Changes: Database references
  • Version 1.2: 2020-01-08
    Changes: Database references
  • Version 1.3: 2020-03-04
    Changes: Data collection
  • Version 1.4: 2023-10-11
    Changes: Data collection, Database references, Refinement description