5e80
The crystal structure of PDEd in complex with inhibitor-2a
Structural highlights
FunctionPDE6D_HUMAN Acts as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude and does so by decreasing the nucleotide dissociation rate. Stabilizes Arl3-GTP by decreasing the nucleotide dissociation (By similarity). Publication Abstract from PubMedThe prenyl-binding protein PDEdelta is crucial for the plasma membrane localization of prenylated Ras. Recently, we have reported that the small-molecule Deltarasin binds to the prenyl-binding pocket of PDEdelta, and impairs Ras enrichment at the plasma membrane, thereby affecting the proliferation of KRas-dependent human pancreatic ductal adenocarcinoma cell lines. Here, using structure-based compound design, we have now identified pyrazolopyridazinones as a novel, unrelated chemotype that binds to the prenyl-binding pocket of PDEdelta with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEdelta inhibitor, named Deltazinone 1, is highly selective, exhibits less unspecific cytotoxicity than the previously reported Deltarasin and demonstrates a high correlation with the phenotypic effect of PDEdelta knockdown in a set of human pancreatic cancer cell lines. Identification of pyrazolopyridazinones as PDEdelta inhibitors.,Papke B, Murarka S, Vogel HA, Martin-Gago P, Kovacevic M, Truxius DC, Fansa EK, Ismail S, Zimmermann G, Heinelt K, Schultz-Fademrecht C, Al Saabi A, Baumann M, Nussbaumer P, Wittinghofer A, Waldmann H, Bastiaens PI Nat Commun. 2016 Apr 20;7:11360. doi: 10.1038/ncomms11360. PMID:27094677[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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