8b9u

Structure of ClpC1 NTD from Mycobacterium tuberculosis

spinqualitylabelsall models 8b9u, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8b9u is a 3 chain structure with sequence from Mycobacterium tuberculosis H37Rv and Nonomuraea sp. MJM5123. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.25Å Ligands: E9M, FMT, MAA, MLE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria. To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism of the antibiotics cyclomarin A and ecumicin. Quantitative proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3. These proteins likely protect the Clp protease from excessive amounts of misfolded proteins or from cyclomarin A, which we show to mimic damaged proteins. To overcome the Clp security system, we developed a BacPROTAC that induces degradation of ClpC1 together with its ClpC2 caretaker. The dual Clp degrader, built from linked cyclomarin A heads, was highly efficient in killing pathogenic Mycobacterium tuberculosis, with >100-fold increased potency over the parent antibiotic. Together, our data reveal Clp scavenger proteins as important proteostasis safeguards and highlight the potential of BacPROTACs as future antibiotics. Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival.,Hoi DM, Junker S, Junk L, Schwechel K, Fischel K, Podlesainski D, Hawkins PME, van Geelen L, Kaschani F, Leodolter J, Morreale FE, Kleine S, Guha S, Rumpel K, Schmiedel VM, Weinstabl H, Meinhart A, Payne RJ, Kaiser M, Hartl M, Boehmelt G, Kazmaier U, Kalscheuer R, Clausen T Cell. 2023 May 11;186(10):2176-2192.e22. doi: 10.1016/j.cell.2023.04.009. Epub , 2023 May 2. PMID:37137307 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA