Objectif
Phosphatidyl inositol phosphates (PIPs) are biosynthesized from phosphatidyl inositol (PI) by the action of PI kinase. The phosphatidylinositol 4-phosphate (PI(4)P) is produced by the action of phosphatidylinositol 4-kinase (PI4K). PIPs are universal markers of intracellular membranes. Their precise spatial and temporal resolution control enables various protein machineries to operate in the correct location at the exact time. PI(4)P is the single most abundant mono phosphoinositide and is the marker of the Golgi and the trans-Golgi network (TGN). It has been reported to play a key role in membrane biogenesis, vesicular transport, lipid dynamics, and protein and lipid sorting in the TGN. Importantly, the replication of several plus RNA viruses, mainly the Hepatitis C virus (HCV), SARS, and poliovirus (PV) depend on PI(4)P. For instance, HCV hijacks PI4K III alpha to generate endoplasmatic reticulum (ER) derived membranous webs that are enriched in PI(4)P and where the replication of HCV takes place. The main goals of this proposal are (i.) to get structural insight into PI(4)P biosynthesis by solving crystal structure of the PI4K kinase domain and/or the full length enzyme (ii.) to solve the crystal structure of the kinase domain in complex with a small molecule inhibitor like the well known PIK93 (iii.) use the structural information to design novel small molecule inhibitors with higher affinity and specificity that could be used as antivirals.
Champ scientifique
Appel à propositions
FP7-PEOPLE-2012-CIG
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Régime de financement
MC-CIG - Support for training and career development of researcher (CIG)Coordinateur
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