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Études moléculaires et structurales - d’un nouveau mode de dimérisation des intégrases rétrovirales pour développer des modulateurs d’oligomérisation ET - de l’intégrase porcine de PERV-A/C en complexe avec son cofacteur cellulaire humain Brd2 dans un contexte de xénotransplantatio

Abstract : Integrase (IN) is an essential enzyme in retroviral replicative cycle, which catalyzes the integration of the viral DNA into the target cell genome. Structural data previously obtained by our team led to rational design of molecules likely to block IN in an inactive oligomeric form. In vitro concerted integration assays made it possible to study their effect on IN enzymatic activity. Pig has an endogenous gammaretrovirus called Porcine Endogenous RetroVirus (PERV) which can be transmitted to humans during xenotransplantation. The aim of the structural study of the recombinant virus PERV-A/C IN is to better understand its mechanism and thus guide the rational design of inhibitors limiting xenozoonosis risk. I modeled the PERV-A/C IN intasome in complex with raltegravir, a drug used for HIV treatment. Then I developed purification protocols to study the isolated and complexed PERV-A/C IN Carboxy-Terminal Domain (CTD) with the human cellular cofactor Brd2. The SAXS envelope of the complex was determined. In parallel, a histone array study, performed with the PERV-A/C IN CTD alone, revealed a specificity profile for modified H2B and H3 histone tails
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Halima Yajjou. Études moléculaires et structurales - d’un nouveau mode de dimérisation des intégrases rétrovirales pour développer des modulateurs d’oligomérisation ET - de l’intégrase porcine de PERV-A/C en complexe avec son cofacteur cellulaire humain Brd2 dans un contexte de xénotransplantatio. Biochimie, Biologie Moléculaire. Université de Lyon, 2017. Français. ⟨NNT : 2017LYSE1035⟩. ⟨tel-01673802⟩

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