4GW8

Human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and Leucettine L41


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 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.P.Knapp, S.Meijer, L.

(2012) J Med Chem 55: 9312-9330

  • 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
Serine/threonine-protein kinase pim-1313Homo sapiensMutation(s): 1 
Gene Names: PIM1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11309 (Homo sapiens)
Explore P11309 
Go to UniProtKB:  P11309
PHAROS:  P11309
GTEx:  ENSG00000137193 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11309
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Consensus peptide (Pimtide)14N/AMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3RA
Query on 3RA

Download Ideal Coordinates CCD File 
C [auth A]5-(1,3-benzodioxol-5-ylmethyl)-2-(phenylamino)-4H-imidazol-4-one
C17 H13 N3 O3
ZDINVWCJHPMIKS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3RA Binding MOAD:  4GW8 IC50: 880 (nM) from 1 assay(s)
PDBBind:  4GW8 IC50: 880 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.006α = 90
b = 98.006β = 90
c = 80.497γ = 120
Software Package:
Software NamePurpose
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
MOSFLMdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-03
    Type: Initial release
  • Version 1.1: 2012-11-21
    Changes: Database references
  • Version 1.2: 2018-01-24
    Changes: Structure summary
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description