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Publication Abstract from PubMed

Bacterial ClpP is a highly conserved, cylindrical, self-compartmentalizing serine protease required for maintaining cellular proteostasis. Small molecule acyldepsipeptides (ADEPs) and activators of self-compartmentalized proteases 1 (ACP1s) cause dysregulation and activation of ClpP, leading to bacterial cell death, highlighting their potential use as novel antibiotics. Structural changes in Neisseria meningitidis and Escherichia coli ClpP upon binding to novel ACP1 and ADEP analogs were probed by X-ray crystallography, methyl-TROSY NMR, and small angle X-ray scattering. ACP1 and ADEP induce distinct conformational changes in the ClpP structure. However, reorganization of electrostatic interaction networks at the ClpP entrance pores is necessary and sufficient for activation. Further activation is achieved by formation of ordered N-terminal axial loops and reduction in the structural heterogeneity of the ClpP cylinder. Activating mutations recapitulate the structural effects of small molecule activator binding. Our data, together with previous findings, provide a structural basis for a unified mechanism of compound-based ClpP activation.

ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores.,Mabanglo MF, Leung E, Vahidi S, Seraphim TV, Eger BT, Bryson S, Bhandari V, Zhou JL, Mao YQ, Rizzolo K, Barghash MM, Goodreid JD, Phanse S, Babu M, Barbosa LRS, Ramos CHI, Batey RA, Kay LE, Pai EF, Houry WA Commun Biol. 2019 Nov 13;2(1):410. doi: 10.1038/s42003-019-0656-3. PMID:31925204^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.