3ZDI | pdb_00003zdi

Glycogen Synthase Kinase 3 Beta complexed with Axin Peptide and Inhibitor 7d


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 
    0.242 (Depositor), 0.230 (DCC) 
  • R-Value Work: 
    0.201 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 
    0.204 (Depositor) 

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 UGJClick on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

3,6-Diamino-4-(2-Halophenyl)-2-Benzoylthieno(2,3-B) Pyridine-5-Carbonitriles are Selective Inhibitors of Plasmodium Falciparum Glycogen Synthase Kinase-3 (Pfgsk-3)

Fugel, W.Oberholzer, A.E.Gschloessl, B.Dzikowski, R.Pressburger, N.Preu, L.Pearl, L.H.Baratte, B.Ratin, M.Okun, I.Doerig, C.Kruggel, S.Lemcke, T.Meijer, L.Kunick, C.

(2013) J Med Chem 56: 264

  • DOI: https://doi.org/10.1021/jm301575n
  • Primary Citation of Related Structures:  
    3ZDI

  • PubMed Abstract: 

    Plasmodium falciparum is the infective agent responsible for malaria tropica. The glycogen synthase kinase-3 of the parasite (PfGSK-3) was suggested as a potential biological target for novel antimalarial drugs. Starting from hit structures identified in a high-throughput screening campaign, 3,6-diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles were discovered as a new class of PfGSK-3 inhibitors. Being less active on GSK-3 homologues of other species, the title compounds showed selectivity in favor of PfGSK-3. Taking into account the X-ray structure of a related molecule in complex with human GSK-3 (HsGSK-3), a model was computed for the comparison of inhibitor complexes with the plasmodial and human enzymes. It was found that subtle differences in the ATP-binding pockets are responsible for the observed PfGSK-3 vs HsGSK-3 selectivity. Representatives of the title compound class exhibited micromolar IC₅₀ values against P. falciparum erythrocyte stage parasites. These results suggest that inhibitors of PfGSK-3 could be developed as potential antimalarial drugs.


  • Organizational Affiliation

    Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GLYCOGEN SYNTHASE KINASE-3 BETA350Homo sapiensMutation(s): 0 
EC: 2.7.11.26 (PDB Primary Data), 2.7.11.1 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P49841 (Homo sapiens)
Explore P49841 
Go to UniProtKB:  P49841
PHAROS:  P49841
GTEx:  ENSG00000082701 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49841
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
AXIN-118Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for O15169 (Homo sapiens)
Explore O15169 
Go to UniProtKB:  O15169
PHAROS:  O15169
GTEx:  ENSG00000103126 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO15169
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
UGJ
Query on UGJ

Download Ideal Coordinates CCD File 
D [auth A]3,6-Diamino-4-(2-chlorophenyl)thieno[2,3-b]pyridine-2,5-dicarbonitrile
C15 H8 Cl N5 S
ZYCDWPCMXHYGRS-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
C [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free:  0.242 (Depositor), 0.230 (DCC) 
  • R-Value Work:  0.201 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 0.204 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.147α = 90
b = 76.157β = 90
c = 86.545γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata 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 UGJClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-12-26
    Type: Initial release
  • Version 1.1: 2013-01-30
    Changes: Database references
  • Version 1.2: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description
  • Version 1.3: 2024-10-09
    Changes: Structure summary