4B7T

Glycogen Synthase Kinase 3 Beta complexed with Axin Peptide and Leucettine L4


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.77 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Selectivity, Cocrystal Structures, and Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors Derived from the Marine Sponge Alkaloid Leucettamine B.

Tahtouh, T.Elkins, J.M.Filippakopoulos, P.Soundararajan, M.Burgy, G.Durieu, E.Cochet, C.Schmid, R.S.Lo, D.C.Delhommel, F.Oberholzer, A.E.Pearl, L.H.Carreaux, F.Bazureau, J.Knapp, S.Meijer, L.

(2012) J Med Chem 55: 9312

  • DOI: https://doi.org/10.1021/jm301034u
  • Primary Citation of Related Structures:  
    4AZE, 4AZF, 4B7T, 4GW8

  • PubMed Abstract: 

    DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimer's disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimer's disease.


  • Organizational Affiliation

    CNRS, "Protein Phosphorylation & Human Disease" Group, Station Biologique, 29680 Roscoff, Bretagne, France.


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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CWT
Query on CWT

Download Ideal Coordinates CCD File 
C [auth A](5Z)-5-(1,3-benzodioxol-5-ylmethylidene)-3-methyl-2-(propan-2-ylamino)imidazol-4-one
C15 H17 N3 O3
ILLXEUXWCCUOCH-WDZFZDKYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.77 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.577α = 90
b = 81.577β = 90
c = 283.654γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-01-30
    Type: Initial release
  • Version 1.1: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description