5JQ3

Crystal structure of Ebola glycoprotein


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.223 

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This is version 2.1 of the entry. See complete history


Literature

Toremifene interacts with and destabilizes the Ebola virus glycoprotein.

Zhao, Y.Ren, J.Harlos, K.Jones, D.M.Zeltina, A.Bowden, T.A.Padilla-Parra, S.Fry, E.E.Stuart, D.I.

(2016) Nature 535: 168-172

  • DOI: https://doi.org/10.1038/nature18615
  • Primary Citation of Related Structures:  
    5JQ3, 5JQ7, 5JQB

  • PubMed Abstract: 

    Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion. GP is thus a primary target for the development of antiviral drugs. Here we report the first, to our knowledge, unliganded structure of EBOV GP, and high-resolution complexes of GP with the anticancer drug toremifene and the painkiller ibuprofen. The high-resolution apo structure gives a more complete and accurate picture of the molecule, and allows conformational changes introduced by antibody and receptor binding to be deciphered. Unexpectedly, both toremifene and ibuprofen bind in a cavity between the attachment (GP1) and fusion (GP2) subunits at the entrance to a large tunnel that links with equivalent tunnels from the other monomers of the trimer at the three-fold axis. Protein–drug interactions with both GP1 and GP2 are predominately hydrophobic. Residues lining the binding site are highly conserved among filoviruses except Marburg virus (MARV), suggesting that MARV may not bind these drugs. Thermal shift assays show up to a 14 °C decrease in the protein melting temperature after toremifene binding, while ibuprofen has only a marginal effect and is a less potent inhibitor. These results suggest that inhibitor binding destabilizes GP and triggers premature release of GP2, thereby preventing fusion between the viral and endosome membranes. Thus, these complex structures reveal the mechanism of inhibition and may guide the development of more powerful anti-EBOV drugs.


  • Organizational Affiliation

    Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, OX3 7BN, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Envelope glycoprotein 1,Envelope glycoprotein 1,Envelope glycoprotein 1332Ebola virus - Mayinga, Zaire, 1976Mutation(s): 1 
Gene Names: GP
UniProt
Find proteins for Q05320 (Zaire ebolavirus (strain Mayinga-76))
Explore Q05320 
Go to UniProtKB:  Q05320
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ05320
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Envelope glycoprotein 2168Ebola virus - Mayinga, Zaire, 1976Mutation(s): 0 
Gene Names: GP
UniProt
Find proteins for Q05320 (Zaire ebolavirus (strain Mayinga-76))
Explore Q05320 
Go to UniProtKB:  Q05320
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ05320
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
C
5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G22768VO
GlyCosmos:  G22768VO
GlyGen:  G22768VO
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.222 
  • R-Value Observed: 0.223 
  • Space Group: H 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 114.258α = 90
b = 114.258β = 90
c = 307.377γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
xia2data reduction
xia2data scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-06-29
    Type: Initial release
  • Version 1.1: 2016-07-13
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary