5AJJ

Crystal structure of variola virus virulence factor F1L in complex with human Bid BH3 domain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Variola Virus F1L is a Bcl-2-Like Protein that Unlike its Vaccinia Virus Counterpart Inhibits Apoptosis Independent of Bim.

Marshall, B.Puthalakath, H.Caria, S.Chugh, S.Doerflinger, M.Colman, P.M.Kvansakul, M.

(2015) Cell Death Dis 6: E1680

  • DOI: https://doi.org/10.1038/cddis.2015.52
  • Primary Citation of Related Structures:  
    5AJJ, 5AJK

  • PubMed Abstract: 

    Subversion of host cell apoptosis is an important survival strategy for viruses to ensure their own proliferation and survival. Certain viruses express proteins homologous in sequence, structure and function to mammalian pro-survival B-cell lymphoma 2 (Bcl-2) proteins, which prevent rapid clearance of infected host cells. In vaccinia virus (VV), the virulence factor F1L was shown to be a potent inhibitor of apoptosis that functions primarily be engaging pro-apoptotic Bim. Variola virus (VAR), the causative agent of smallpox, harbors a homolog of F1L of unknown function. We show that VAR F1L is a potent inhibitor of apoptosis, and unlike all other characterized anti-apoptotic Bcl-2 family members lacks affinity for the Bim Bcl-2 homology 3 (BH3) domain. Instead, VAR F1L engages Bid BH3 as well as Bak and Bax BH3 domains. Unlike its VV homolog, variola F1L only protects against Bax-mediated apoptosis in cellular assays. Crystal structures of variola F1L bound to Bid and Bak BH3 domains reveal that variola F1L forms a domain-swapped Bcl-2 fold, which accommodates Bid and Bak BH3 in the canonical Bcl-2-binding groove, in a manner similar to VV F1L. Despite the observed conservation of structure and sequence, variola F1L inhibits apoptosis using a startlingly different mechanism compared with its VV counterpart. Our results suggest that unlike during VV infection, Bim neutralization may not be required during VAR infection. As molecular determinants for the human-specific tropism of VAR remain essentially unknown, identification of a different mechanism of action and utilization of host factors used by a VAR virulence factor compared with its VV homolog suggest that studying VAR directly may be essential to understand its unique tropism.


  • Organizational Affiliation

    1] Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, 3086 Victoria, Australia [2] La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Melbourne, 3086 Victoria, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HOMOLOG OF VACCINIA VIRUS CDS F1L PUTATIVE168Variola virusMutation(s): 0 
UniProt
Find proteins for Q85365 (Variola virus)
Explore Q85365 
Go to UniProtKB:  Q85365
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ85365
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
BH3-INTERACTING DOMAIN DEATH AGONIST34Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P55957 (Homo sapiens)
Explore P55957 
Go to UniProtKB:  P55957
PHAROS:  P55957
GTEx:  ENSG00000015475 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55957
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 
  • Space Group: F 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.094α = 90
b = 112.318β = 90
c = 117.178γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-25
    Type: Initial release
  • Version 1.1: 2015-04-08
    Changes: Atomic model, Derived calculations, Other
  • Version 1.2: 2015-07-29
    Changes: Source and taxonomy
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description