RCSB PDB - 8E5U: Co-crystal structure of Chaetomium glucosidase with compound 9

 8E5U

Co-crystal structure of Chaetomium glucosidase with compound 9


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.33 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted UPHClick on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum alpha-Glucosidase I with Anti-SARS-CoV-2 Activity.

Karade, S.S.Franco, E.J.Rojas, A.C.Hanrahan, K.C.Kolesnikov, A.Yu, W.MacKerell Jr., A.D.Hill, D.C.Weber, D.J.Brown, A.N.Treston, A.M.Mariuzza, R.A.

(2023) J Med Chem 66: 2744-2760

  • DOI: https://doi.org/10.1021/acs.jmedchem.2c01750
  • Primary Citation of Related Structures:  
    7R6J, 7RD2, 7REV, 8E3J, 8E3P, 8E4I, 8E4K, 8E4Z, 8E5U, 8E6G, 8ECW, 8EGV, 8EHP, 8EID, 8EKN, 8ELE, 8EPJ, 8EPO, 8EPR, 8EQ7, 8EQX, 8ER4, 8ETL, 8ETO, 8EUD, 8EUR, 8EUT, 8EUX

  • PubMed Abstract: 

    Enveloped viruses depend on the host endoplasmic reticulum (ER) quality control (QC) machinery for proper glycoprotein folding. The endoplasmic reticulum quality control (ERQC) enzyme α-glucosidase I (α-GluI) is an attractive target for developing broad-spectrum antivirals. We synthesized 28 inhibitors designed to interact with all four subsites of the α-GluI active site. These inhibitors are derivatives of the iminosugars 1-deoxynojirimycin (1-DNJ) and valiolamine. Crystal structures of ER α-GluI bound to 25 1-DNJ and three valiolamine derivatives revealed the basis for inhibitory potency. We established the structure-activity relationship (SAR) and used the Site Identification by Ligand Competitive Saturation (SILCS) method to develop a model for predicting α-GluI inhibition. We screened the compounds against SARS-CoV-2 in vitro to identify those with greater antiviral activity than the benchmark α-glucosidase inhibitor UV-4. These host-targeting compounds are candidates for investigation in animal models of SARS-CoV-2 and for testing against other viruses that rely on ERQC for correct glycoprotein folding.


  • Organizational Affiliation

    University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Chaetomium alpha glucosidase
A, B
819Thermochaetoides thermophila DSM 1495Mutation(s): 0 
Gene Names: CTHT_0061620
EC: 3.2.1.106
UniProt
Find proteins for G0SFD1 (Chaetomium thermophilum (strain DSM 1495 / CBS 144.50 / IMI 039719))
Explore G0SFD1 
Go to UniProtKB:  G0SFD1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupG0SFD1
Glycosylation
Glycosylation Sites: 1
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
UPH (Subject of Investigation/LOI)
Query on UPH

Download Ideal Coordinates CCD File 
C [auth A],
M [auth B]
(2R,3R,4R,5S)-2-(hydroxymethyl)-1-(6-{2-nitro-4-[(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl]anilino}hexyl)piperidine-3,4,5-triol
C24 H38 N4 O7
QGCBQROIBSZCHP-OAOHXRHQSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
L [auth B]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
BTB
Query on BTB

Download Ideal Coordinates CCD File 
K [auth B]2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL
C8 H19 N O5
OWMVSZAMULFTJU-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.33 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 135.934α = 90
b = 179.587β = 90
c = 180.19γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted UPHClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2023-02-22
    Type: Initial release
  • Version 1.1: 2023-03-01
    Changes: Database references
  • Version 1.2: 2023-10-25
    Changes: Data collection, Refinement description
  • Version 1.3: 2024-10-30
    Changes: Structure summary