5E80

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

5E80 の概要

• エントリーDOI: 10.2210/pdb5e80/pdb
• 分子名称: 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)
• 機能のキーワード: prenyl binding protein /inhibitor, immunoglobulin-like beta-sandwich, gdi-like solubilizing factor, lipid binding protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytosol : O43924
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 35403.38

構造登録者

Ismail, S.,Fansa, E.K.,Murarka, S.,Wittinghofer, A. (登録日: 2015-10-13, 公開日: 2016-05-04, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.6 Å)