ClpP is a cylindrical tetradecameric serine protease whose activity is regulated by the unfoldase ATP-dependent chaperones ClpX and ClpA of the AAA+ superfamily. The chaperones act to select substrate proteins, unfold them, and then thread them into the ClpP cylinder for degradation. ClpP can only degrade small peptides on its own. Structural and functional studies from my group have elucidated the mechanism of function of the ClpXP chaperone-protease system. These studies highlighted the importance of protein dynamics in this system. More recently, we used ClpP as a target in a high-throughput screen for compounds, which activate the protease and allow it to degrade larger proteins, hence, abolishing the specificity arising from the ATP-dependent chaperones. Our screen resulted in five structurally distinct compounds, which we designate as activators of self-compartmentalizing proteases 1 to 5 (ACP 1 to 5). The compounds are found to stabilize the ClpP double ring structure. The ACP1 chemical structure was considered to have drug-like characteristics and was further optimized to give analogs with bactericidal activity. Hence, the ACPs represent new classes of compounds that can activate ClpP and that can be developed as potential novel antibiotics.


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