A09 Sieber: Small molecule induced conformational control of protein function and activity
Caseinolytic protease P (ClpP) represents a prominent serine protease responsible for the degradation of damaged proteins. ClpP assembles in a barrel-shaped tetradecameric complex that exists in different conformational states. We aim to unravel ClpP complex disassembly via active site traps to form irreversible acyl-enzyme intermediates with dedicated inhibitors. This ClpP trap will be used to gain first insights into the conformational switching of beta-lactones as well as phenylester inhibitors. Inspired by our recent studies on the overall structural composition of Listeria ClpP1/2, we will expand our methodology towards the functional and mechanistic exploitation of Pseudomonas ClpP1, ClpP2 and ClpP3 and investigate which principles of conformational control are applied by this more complex system. All together, these studies will complement our current understanding of this versatile and highly dynamic bacterial protease.