6F6S

CRYSTAL STRUCTURE OF EBOLAVIRUS GLYCOPROTEIN IN COMPLEX WITH benztropine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.208 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection.

Ren, J.Zhao, Y.Fry, E.E.Stuart, D.I.

(2018) J Med Chem 61: 724-733

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01249
  • Primary Citation of Related Structures:  
    6F5U, 6F6I, 6F6N, 6F6S

  • PubMed Abstract: 

    Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as reported for the anticancer drug toremifene and the painkiller ibuprofen, which bind in the same large cavity on the glycoprotein. Crystal structures show that the position of binding and the mode of interaction within the pocket vary significantly between these compounds. The binding constants (K d ) determined by thermal shift assay correlate with the protein-inhibitor interactions as well as with the antiviral activities determined by virus cell entry assays, supporting the hypothesis that these drugs inhibit viral entry by binding the glycoprotein and destabilizing the prefusion conformation. Details of the protein-inhibitor interactions of these complexes and their relation with binding affinity may facilitate the design of more potent inhibitors.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Envelope glycoprotein,Envelope glycoprotein,GP1329Ebola virus - Mayinga, Zaire, 1976Ebola virusMutation(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 glycoprotein168Ebola virusMutation(s): 1 
Gene Names: 
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
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CXQ
Query on CXQ

Download Ideal Coordinates CCD File 
I [auth A],
U [auth B]
benztropine
C21 H25 N O
GIJXKZJWITVLHI-PMOLBWCYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A],
F [auth A],
Q [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A],
R [auth B],
S [auth B],
T [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
AA [auth B]
J [auth A]
K [auth A]
L [auth A]
M [auth A]
AA [auth B],
J [auth A],
K [auth A],
L [auth A],
M [auth A],
N [auth A],
O [auth A],
P [auth A],
V [auth B],
W [auth B],
X [auth B],
Y [auth B],
Z [auth B]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
CXQ Binding MOAD:  6F6S Kd: 1.30e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.208 
  • Space Group: H 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 114.379α = 90
b = 114.379β = 90
c = 305.749γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
xia2data reduction
xia2data scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
UKUnited KingdomMR/N00065X/1

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-03
    Type: Initial release
  • Version 1.1: 2018-01-24
    Changes: Database references
  • Version 1.2: 2018-02-21
    Changes: Database references
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 1.4: 2024-01-17
    Changes: Data collection, Database references, Refinement description, Structure summary