4JV8

The crystal structure of PDE6D in complex with rac-S1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.181 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Small molecule inhibition of the KRAS PDEd interaction impairs oncogenic KRAS signalling

Zimmermann, G.Papke, B.Ismail, S.Vartak, N.Chandra, A.Hoffmann, M.Hahn, S.A.Triola, G.Wittinghofer, A.Bastiaens, P.I.Waldmann, H.

(2013) Nature 497: 638-642

  • DOI: https://doi.org/10.1038/nature12205
  • Primary Citation of Related Structures:  
    4JV6, 4JV8, 4JVB, 4JVF

  • PubMed Abstract: 

    The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEδ interaction that selectively bind to the prenyl-binding pocket of PDEδ with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.


  • Organizational Affiliation

    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit deltaA [auth B]152Homo sapiensMutation(s): 0 
Gene Names: PDE6DPDED
UniProt & NIH Common Fund Data Resources
Find proteins for O43924 (Homo sapiens)
Explore O43924 
Go to UniProtKB:  O43924
PHAROS:  O43924
GTEx:  ENSG00000156973 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO43924
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1M1
Query on 1M1

Download Ideal Coordinates CCD File 
B,
C [auth B]
(6R)-6-(pyridin-2-yl)-5,6-dihydrobenzimidazo[1,2-c]quinazoline
C19 H14 N4
ZMZZAQWHHFSQPH-LJQANCHMSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1M1 PDBBind:  4JV8 Kd: 1420 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.181 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.97α = 90
b = 55.97β = 90
c = 115.56γ = 120
Software Package:
Software NamePurpose
PROdata collection
MOLREPphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-22
    Type: Initial release
  • Version 1.1: 2013-06-05
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description