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Structural studies of host-virus interactions looking at two examples: the innate immunity receptor RIG-I and the influenza virus RNA polymerase endonuclease

Eva Kowalinski 1
1 Cusack
EMBL - European Molecular Biology Laboratory [Heidelberg]
Abstract : The first line of defense against invading pathogens in the human body is the innate im- mune system. Astonishingly, with only a handful of different pathogen recognition recep- tors (around 50), the innate immune system is able to detect a remarkably broad variety of pathogen specific molecules to trigger protective pathways and to activate the adaptive immune system. In the case of intruding viruses, two families of pattern recognition re- ceptors (PRRs) are active: retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and Toll-like receptors (TLRs). The family of RIG-I like receptors includes the proteins RIG-I, MDA5 and LGP2, which recognize viral RNA in the cytosol. In the first part of this thesis, aspects of the RIG-I pathway are discussed: With which RNA does RIG-I interact and how? Does the oligomeric state of RIG-I change upon RNA binding in or- der to trigger signaling? How is RIG-I regulated by ubiquitin and its E3 ubiquitin ligase TRIM25? The structure of the PRYSPRY domain of TRIM25, its putative RIG-I binding domain, will be presented. Furthermore, preliminary work on the second receptor MDA5 in complex with parainfluenza virus V, which inhibits the MDA5 pathway, protein will be shown. One of the activators of the receptor RIG-I is the RNA of influenza virus. Influenza viruses belong to the family of Orthomyxoviridae that affect birds and mammals and spread in seasonal epidemics. In pandemic years, this can result in up to millions of deaths worldwide, underlining the need for research on efficient novel anti-viral drugs. In the second part of the thesis (appended as an article manuscript), the A/California/04/2009- H1N1 "swine flu" influenza RNA polymerase will be investigated as a novel antiviral drug target. Crystal structures of the endonuclease domain (PA-Nter) of the polymerase with four different inhibitors are presented. Moreover, the atomic structures of H1N1 PA-Nter with rUMP and dTMP, elements of the nucleic acid substrate, in the active site are discussed. These high resolution structures will serve as a basis for structure based inhibitor optimization.
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Eva Kowalinski. Structural studies of host-virus interactions looking at two examples: the innate immunity receptor RIG-I and the influenza virus RNA polymerase endonuclease. Biochemistry, Molecular Biology. Université Joseph-Fourier - Grenoble I, 2010. English. ⟨tel-00752678⟩

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