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Origine et évolution des récepteurs nucléaires et étude structurale du premier stéroïdien, ERR

Abstract : Nuclear receptors (NRs) are transcription factors which bind to specific DNA sequences and activate gene transcription in response to the binding of specific ligands. Among all of the RNs involved in the etiology of cancers, ERR estrogen receptors play an important role in breast, ovarian, colon, endometrial and prostate cancers. This NR is said to be orphan because it does not have a natural ligand known to date. Using an integrative structural biology approach combining cryo-electron microscopy, bioinformatics and evolution, my PhD work focused on the structural study of ERR and the origin and evolution of RNs. In this context, three informatic tools have been developed. The results obtained allowed, on the one hand, the revision of fundamental knowledge on the origin of nuclear receptors and their evolution. On the other hand, structural study of ERR allow us to acquire new data on topology of steroid nuclear receptors fixed on an element of ERRE / ERE response as well as on the allosteric mechanism of the binding of the coactivator PGC-1α on the dimer of ERR. The resolution of the complex at the atomic scale by cryo-electron microscopy will open the way towards the design of new therapeutic molecules.
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Brice Beinsteiner. Origine et évolution des récepteurs nucléaires et étude structurale du premier stéroïdien, ERR. Biologie structurale [q-bio.BM]. Université de Strasbourg, 2018. Français. ⟨NNT : 2018STRAJ099⟩. ⟨tel-02918003⟩

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