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PDBsum entry 4jvb
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Protein binding/inhibitor
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PDB id
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4jvb
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PDB id:
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| Name: |
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Protein binding/inhibitor
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Title:
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Crystal structure of pde6d in complex with the inhibitor rac-2
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Structure:
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Retinal rod rhodopsin-sensitive cgmp 3',5'-cyclic phosphodiesterase subunit delta. Chain: b. Synonym: gmp-pde delta, protein p17. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: pde6d, pded. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.75Å
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R-factor:
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0.190
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R-free:
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0.236
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Authors:
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Z.Gunther,B.Papke,S.Ismail,N.Vartak,A.Chandra,M.Hoffmann,S.Hahn, G.Triola,A.Wittinghofer,P.Bastiaens,H.Waldmann
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Key ref:
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G.Zimmermann
et al.
(2013).
Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling.
Nature,
497,
638-642.
PubMed id:
DOI:
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Date:
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25-Mar-13
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Release date:
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22-May-13
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PROCHECK
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Headers
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References
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O43924
(PDE6D_HUMAN) -
Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta from Homo sapiens
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Seq:
Struc:
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150 a.a.
146 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Nature
497:638-642
(2013)
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PubMed id:
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Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling.
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G.Zimmermann,
B.Papke,
S.Ismail,
N.Vartak,
A.Chandra,
M.Hoffmann,
S.A.Hahn,
G.Triola,
A.Wittinghofer,
P.I.Bastiaens,
H.Waldmann.
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ABSTRACT
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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.
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Links
