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Molecular Basis of ClpP Protease Activation by Small Molecules

Bacterial ClpP is a highly conserved, self‐compartmentalizing, cylindrical serine protease required for maintaining cellular proteostasis. Acyldepsipeptides (ADEPs) and activators of self‐compartmentalized proteases (ACPs) are small molecules that cause the dysregulation and activation of ClpP, which leads to bacterial cell death, highlighting their potential use as novel antibiotics. However, the molecular basis of ClpP activation by small molecules remains undetermined. Structural changes in ClpP from Neisseria meningitidis and Escherichia coli upon binding to novel ACP and ADEP analogs were probed by X‐ray crystallography, methyl‐TROSY NMR, hydrogen‐deuterium exchange, and small angle X‐ray scattering. ACP and ADEP were found to induce distinct conformational changes in the tertiary structure of ClpP. However, ordered N‐terminal axial loops, reorganization of the hydrogen bonding network at the entrance pore of ClpP, and reduced structural heterogeneity of the ClpP cylinder are common features of activator‐bound complexes. Activated ClpP mutants were obtained that recapitulate these effects. Based on our data, we propose a unified mechanism for compound‐based ClpP activation.