6G95

Crystal structure of Ebolavirus glycoprotein in complex with thioridazine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.31 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.185 

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Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Structures of Ebola Virus Glycoprotein Complexes with Tricyclic Antidepressant and Antipsychotic Drugs.

Zhao, Y.Ren, J.Fry, E.E.Xiao, J.Townsend, A.R.Stuart, D.I.

(2018) J Med Chem 61: 4938-4945

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00350
  • Primary Citation of Related Structures:  
    6G95, 6G9B, 6G9I

  • PubMed Abstract: 

    A large number of Food and Drug Administration (FDA)-approved drugs have been found to inhibit the cell entry of Ebola virus (EBOV). However, since these drugs have various primary pharmacological targets, their mechanisms of action against EBOV remain largely unknown. We have previously shown that six FDA-approved drugs inhibit EBOV infection by interacting with and destabilizing the viral glycoprotein (GP). Here we show that antidepressants imipramine and clomipramine and antipsychotic drug thioridazine also directly interact with EBOV GP and determine the mode of interaction by crystallographic analysis of the complexes. The compounds bind within the same pocket as observed for other, chemically divergent complexes but with different binding modes. These details should be of value for the development of potent EBOV 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 glycoprotein330Ebola 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 glycoprotein168Ebola 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
Oligosaccharides

Help

Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
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
4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G22573RC
GlyCosmos:  G22573RC
GlyGen:  G22573RC
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RTZ (Subject of Investigation/LOI)
Query on RTZ

Download Ideal Coordinates CCD File 
O [auth B]10-{2-[(2R)-1-methylpiperidin-2-yl]ethyl}-2-(methylsulfanyl)-10H-phenothiazine
C21 H26 N2 S2
KLBQZWRITKRQQV-MRXNPFEDSA-N
NAG
Query on NAG

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

Download Ideal Coordinates CCD File 
H [auth A],
J [auth A],
L [auth B],
M [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
I [auth A],
K [auth A],
N [auth B]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.31 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.185 
  • Space Group: H 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 113.97α = 90
b = 113.97β = 90
c = 305.66γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
xia2data reduction
xia2data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Medical Research Council (United Kingdom)United Kingdom--

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-23
    Type: Initial release
  • Version 1.1: 2018-06-27
    Changes: Data collection, Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary