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Structure of the ClpP:ADEP4-complex from Staphylococcus aureus (open state)Structure of the ClpP:ADEP4-complex from Staphylococcus aureus (open state)
Structural highlights
FunctionCLPP_STAA8 Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity). Publication Abstract from PubMedADEP (acyldepsipeptide) is an exploratory antibiotic with a novel mechanism of action. ClpP, the proteolytic core of the caseinolytic protease, is deregulated towards unrestrained proteolysis. Here, we report on the mechanism of ADEP resistance in Firmicutes, as this bacterial phylum contains important pathogens to be potentially targeted by future ADEP therapy. For Staphylococcus aureus , Bacillus subtilis , enterococci and streptococci, spontaneous ADEP-resistant mutants were selected in vitro at a rate of 10 -6 . All isolates carried mutations in clpP . Characterised mutated S. aureus ClpP proteins were out-of-function and provide insight into the operation mode of ClpP. For molecular insights, crystal structures of S. aureus ClpP bound to ADEP4 were determined. Well-resolved N-terminal domains in the apo structure allow to follow the pore-gating mechanism. The collection of mutations presented here indicates residues relevant for ClpP function and suggests that ADEP-resistance will occur at a lower rate during the infection process. Functional characterisation of ClpP mutations conferring resistance to acyldepsipeptide antibiotics in Firmicutes.,Malik IT, Pereira R, Vielberg MT, Mayer C, Straetener J, Thomy D, Famulla K, Castro H, Sass P, Groll M, Brotz-Oesterhelt H Chembiochem. 2020 Mar 17. doi: 10.1002/cbic.201900787. PMID:32181548[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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