5E80

The crystal structure of PDEd in complex with inhibitor-2a

Summary for 5E80

• Entry DOI: 10.2210/pdb5e80/pdb
• Descriptor: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, N-(3-chloro-2-methylphenyl)-4-(3,4-dimethyl-7-oxo-2-phenyl-2,7-dihydro-6H-pyrazolo[3,4-d]pyridazin-6-yl)butanamide (3 entities in total)
• Functional Keywords: prenyl binding protein /inhibitor, immunoglobulin-like beta-sandwich, gdi-like solubilizing factor, lipid binding protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol : O43924
• Total number of polymer chains: 2
• Total formula weight: 35403.38

Authors

Ismail, S.,Fansa, E.K.,Murarka, S.,Wittinghofer, A. (deposition date: 2015-10-13, release date: 2016-05-04, Last modification date: 2024-01-10)

Primary citation

Papke, B.,Murarka, S.,Vogel, H.A.,Martin-Gago, P.,Kovacevic, M.,Truxius, D.C.,Fansa, E.K.,Ismail, S.,Zimmermann, G.,Heinelt, K.,Schultz-Fademrecht, C.,Al Saabi, A.,Baumann, M.,Nussbaumer, P.,Wittinghofer, A.,Waldmann, H.,Bastiaens, P.I.
Identification of pyrazolopyridazinones as PDE delta inhibitors.
Nat Commun, 7:11360-11360, 2016

PubMed Abstract: The prenyl-binding protein PDEδ 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 PDEδ, 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 PDEδ with high affinity, thereby displacing prenylated Ras proteins in cells. Our results show that the new PDEδ 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 PDEδ knockdown in a set of human pancreatic cancer cell lines.

PubMed: 27094677
DOI: 10.1038/ncomms11360

Experimental method

X-RAY DIFFRACTION (2.6 Å)