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Compréhension des mécanismes de complexation de l'uranyle par les molécules du vivant : élaboration de peptides biomimétiques chélatants pour la détoxification

Abstract : Heavy metals, especially actinides, are toxic for humans. Understanding the mechanisms responsible for their toxicity is an important field of research in toxicology. Uranyl toxicity is still not well understood. The understanding of uranyl interactions at the molecular level is necessary to predict its chemical toxicity and to develop efficient chelating agents. This work aims at identifying uranyl binding sites in proteins and key factors that govern these interactions. To obtain thermodynamic and structural data, strategies were developed to study two proteins predicted as major uranyl targets which present different structures and properties. We took advantage of fetuin-A structure and studied the two structured domain of the protein by complementary physico-chemical methods including multidimensional NMR spectroscopy to acquire structural information on uranyl binding sites in this protein. In order to elucidate interactions between the metal and disordered phosphorylated proteins such as osteopontin, we designed peptides preorganized in β-sheet optimized to coordinate uranyl cation. We introduced amino acids containing phosphate groups and demonstrated that these peptides are relevant models to mimic uranyl binding sites found in phosphorylated proteins. Biomolecules display different structures and properties which may constitute an obstacle to affinity studies. A tool based on a non-natural fluorescent probe was developed to investigate and compare uranyl targets affinities.
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Fanny Laporte. Compréhension des mécanismes de complexation de l'uranyle par les molécules du vivant : élaboration de peptides biomimétiques chélatants pour la détoxification. Biochimie, Biologie Moléculaire. Université Grenoble Alpes, 2017. Français. ⟨NNT : 2017GREAV038⟩. ⟨tel-02963639⟩

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