title: From Peptide Aptamers to Inhibitors of FUR, Bacterial Transcriptional Regulator of Iron Homeostasis and Virulence.
abstract: FUR (Ferric Uptake Regulator) protein is a global transcriptional regulator that senses iron status and controls the expression of genes involved in iron homeostasis, virulence, and oxidative stress. Ubiquitous in Gram-negative bacteria and absent in eukaryotes, FUR is an attractive antivirulence target since the inactivation of the fur gene in various pathogens attenuates their virulence. The characterization of 13-aa-long anti-FUR linear peptides derived from the variable part of the anti-FUR peptide aptamers, that were previously shown to decrease pathogenic E. coli strain virulence in a fly infection model, is described herein. Modeling, docking, and experimental approaches in vitro (activity and interaction assays, mutations) and in cells (yeast two-hybrid assays) were combined to characterize the interactions of the peptides with FUR, and to understand their mechanism of inhibition. As a result, reliable structure models of two peptide-FUR complexes are given. Inhibition sites are mapped in the groove between the two FUR subunits where DNA should also bind. Another peptide behaves differently and interferes with the dimerization itself. These results define these novel small peptide inhibitors as lead compounds for inhibition of the FUR transcription factor.
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.
authors.forename: Cheickna
authors.initials: C
authors.lastname: Cissé
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Vitale
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.
authors.forename: Aynur
authors.initials: A
authors.lastname: Ahmadova
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, DCM UMR 5250, F-38000 Grenoble, France.|CNRS, DCM UMR 5250, F-38000 Grenoble, France.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Degardin
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Pérard
authors.affiliation: P2I2 Group, Protein Phosphorylation and Human Disease Unit, CNRS Unité de Service et de Recherche USR3151, Station Biologique de Roscoff, F-29680 Roscoff, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Colas
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Miras
authors.affiliation: Univ. Grenoble Alpes, DCM UMR 5250, F-38000 Grenoble, France.|CNRS, DCM UMR 5250, F-38000 Grenoble, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Boturyn
authors.affiliation: Univ. Grenoble Alpes, IBS, F-38044 Grenoble, France.|CNRS, IBS, F-38044 Grenoble, France.|CEA, IBS, F-38044 Grenoble, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Covès
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Crouzy
authors.affiliation: CNRS, Laboratoire de Chimie et Biologie des Métaux (LCBM) UMR 5249 CNRS-CEA-UJF, F-38054 Grenoble, France.|CEA, LCBM, F-38054 Grenoble, France.|Univ. Grenoble Alpes, LCBM, F-38054 Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Michaud-Soret
mesh_terms: D052158:Aptamers, Peptide / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004926:Escherichia coli / Q000378:metabolism* / Q000472:pathogenicity; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D062105:Molecular Docking Simulation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D020798:Two-Hybrid System Techniques; D014774:Virulence
chemical_list: D052158:Aptamers, Peptide; D001426:Bacterial Proteins; D012097:Repressor Proteins; C068477:ferric uptake regulating proteins, bacterial; D007501:Iron