title: Yeast as a tool to select inhibitors of the cullin deneddylating enzyme Csn5.
abstract: The CSN complex plays a key role in various cellular pathways: through a metalloprotease activity of its Csn5 deneddylating enzyme, it regulates the activity of Cullin-RING ligases (CRLs). Indeed, Csn5 has been found amplified in many tumors, but, due to its pleiotropic effects, it is difficult to dissect its function and the involvement in cancer progression. Moreover, while growing evidences point to the neddylation function as a good target for drug development; specific inhibitors have not yet been developed for the CSN. Here, we propose the yeast Saccharomyces cerevisiae as a model system to screen libraries of small molecules as inhibitors of cullins deneddylation, taking advantage of the unique feature of this organism to survive without a functional CSN5 gene and to accumulate a fully neddylated cullin substrate. By combining molecular modeling and simple genetic tools, we were able to identify two small molecular fragments as selective inhibitors of Csn5 deneddylation function.
authors.affiliation: a Istituto Pasteur Fondazione Cenci Bolognetti, Department of Biology and Biotechnology, Sapienza University of Rome , Rome , Italy .|b Associazione Gian Franco Lupo "Un sorriso alla vita" Onlus, U.O.D. Laboratorio di Citogenetica e Genetica Molecolare, ASM Matera , Italy .
authors.forename: Angela
authors.initials: A
authors.lastname: Cirigliano
authors.affiliation: a Istituto Pasteur Fondazione Cenci Bolognetti, Department of Biology and Biotechnology, Sapienza University of Rome , Rome , Italy .
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stirpe
authors.affiliation: c Dipartimento di Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy .
authors.forename: Sergio
authors.initials: S
authors.lastname: Menta
authors.affiliation: d Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia , Rome , Italy , and.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.affiliation: b Associazione Gian Franco Lupo "Un sorriso alla vita" Onlus, U.O.D. Laboratorio di Citogenetica e Genetica Molecolare, ASM Matera , Italy .
authors.forename: Domenico
authors.initials: D
authors.lastname: Dell'Edera
authors.affiliation: e Department of Biology and Environment , Faculty of Natural Sciences, University of Haifa , Oranim , Kiryat Tivon , Israel.
authors.forename: Elah
authors.initials: E
authors.lastname: Pick
authors.affiliation: a Istituto Pasteur Fondazione Cenci Bolognetti, Department of Biology and Biotechnology, Sapienza University of Rome , Rome , Italy .
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Negri
authors.affiliation: c Dipartimento di Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy .
authors.forename: Bruno
authors.initials: B
authors.lastname: Botta
authors.affiliation: a Istituto Pasteur Fondazione Cenci Bolognetti, Department of Biology and Biotechnology, Sapienza University of Rome , Rome , Italy .
authors.forename: Teresa
authors.initials: T
authors.lastname: Rinaldi
mesh_terms: D000075686:COP9 Signalosome Complex; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D056004:Molecular Dynamics Simulation; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors*
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D000075686:COP9 Signalosome Complex; D008666:Metalloendopeptidases; C468276:Rri1 protein, S cerevisiae
keywords: CSN5/Jab1; deneddylation; fragment-based drug design; inhibitors; yeast