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Mechanisms of Translation Regulation

Understanding Bacterial Pathogenesis - ribosome as a stress sensor

Understanding Bacterial Pathogenesis

In bacteria, the stringent response is a key driver of virulence and antibiotic resistance. In response to cellular stresses, such as nutrient deprivation, RelA or its homologs (RSH proteins) initiate the stringent response by synthesizing small-molecule 'alarmones' collectively called (p)ppGpp (guanosine pentaphosphate and guanosine tetraphosphate). Accumulation of (p)ppGpp allows cells to adapt to stress conditions. Understanding the molecular mechanism of stringent response initiation - via RelA activation - may guide the development of new antibacterial therapeutics. We visualized several cryo-EM structures of RelA on the bacterial 70S ribosome, resolving distinct conformational states in a single sample. They show how deacylated tRNA - which accumulates when stressed bacteria are deprived of amino acids - orders RelA to turn the stringent response on. The dynamics of the tRNA (A/R tRNA) shows how the ribosome selects for the correct (cognate) tRNA by rearrangements in the small (30S) subunit (Loveland et al. "Ribosomeā€¢RelA structures reveal the mechanism of stringent response activation". eLife. 2016). 
Click on the image above to see an animation showing rearrangements among RelA-bound ribosome structures and tRNA accommodation in the A site.