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PDBsum entry 4jv8

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protein ligands links
Protein binding/inhibitor PDB id
4jv8
Jmol
Contents
Protein chain
147 a.a.
Ligands
1M1 ×2
Waters ×251
PDB id:
4jv8
Name: Protein binding/inhibitor
Title: The crystal structure of pde6d in complex with rac-s1
Structure: Retinal rod rhodopsin-sensitive cgmp 3',5'-cyclic phosphodiesterase subunit delta. Chain: b. Synonym: gmp-pde delta, protein p17. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pde6d, pded. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.45Å     R-factor:   0.181     R-free:   0.209
Authors: Z.Gunther,B.Papke,S.Ismail,N.Vartak,A.Chandra,M.Hoffmann,S.H G.Triola,A.Wittinghofer,P.Bastiaens,H.Waldmann
Key ref: G.Zimmermann et al. (2013). Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature, 497, 638-642. PubMed id: 23698361 DOI: 10.1038/nature12205
Date:
25-Mar-13     Release date:   22-May-13    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
O43924  (PDE6D_HUMAN) -  Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta
Seq:
Struc:
150 a.a.
147 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   5 terms 
  Biological process     metabolic process   5 terms 
  Biochemical function     protein binding     4 terms  

 

 
DOI no: 10.1038/nature12205 Nature 497:638-642 (2013)
PubMed id: 23698361  
 
 
Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling.
G.Zimmermann, B.Papke, S.Ismail, N.Vartak, A.Chandra, M.Hoffmann, S.A.Hahn, G.Triola, A.Wittinghofer, P.I.Bastiaens, H.Waldmann.
 
  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.