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The development of new therapeutics against bacterial infections has aroused great interest over the last years in the context of drug resistance The starting-point in the pursuit of new antibiotics for which bacterial resistance mechanisms do not exist is the identification of novel cellular targets Genetics studies in the early 2000s have identified engA as a conserved bacterial gene whose product is a GTPase that could represent a potential drug target it is conserved among bacteria essential for cell survival and absent in humans Since EngA acts as an assembly factor for the bacterial ribosome one of our aims was to develop an assay to screen inhibitors of the EngA-ribosome interactions These interactions are modulated by EngA conformational changes that are in turn triggered by the binding of different nucleotides to the catalytic G-domain As the interplay between all these events in bacteria is still not resolved we have used a multi-technique approach to explore these questions in order to obtain useful information for the setting up of a robust screening assay SAXS and limited proteolysis showed a conformational change occurring in solution upon addition of either di- or tri-phosphate nucleotides While model validation analysis confirmed the GDP-bound conformation the GTP-bound state does not match any known EngA structure Binding studies have revealed modulation of interactions by different nucleotide-bound states Furthermore response to nucleotides occurs at high concentrations suggesting that the role of EngA in promoting ribosome assembly could be monitored by the intracellular nucleotide concentration Efforts on identifying the GTP-bound state 3D structure by crystallography have resulted in EngA structures in different crystal forms Although all the obtained structures represent the GDP-bound state packing analysis has revealed conserved crystal contacts that can potentially stabilise this conformation during nucleation Specific mutations aiming at disrupting these contacts may help to promote crystallisation of alternative conformations Cryo-EM investigation has been initiated in order to obtain the structure of the B subtilis EngA 50S complex So far an electron density map at 6 4 resolution has been obtained and its interpretation is underway

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Understanding ribosome binding interactions and conformational changes of the EngA bacterial GTPase, a potential target ...

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