8a8v

Mycobacterium tuberculosis ClpC1 hexamer structure bound to the natural product antibiotic Cyclomarin

spinqualitylabelsall models 8a8v, resolution 3.34Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8a8v is a 7 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.34Å Ligands: ADP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CLPC1_MYCTU ATP-dependent specificity component of the Clp protease. It directs the protease to specific substrates. Can perform chaperone functions in the absence of ClpP (By similarity). Degrades anti-sigma-E factor RseA in the presence of ClpP2. Publication Abstract from PubMed The unfoldase ClpC1 is one of the most exciting drug targets against tuberculosis. This AAA+ unfoldase works in cooperation with the ClpP1P2 protease and is the target of at least four natural product antibiotics: cyclomarin, ecumicin, lassomycin, and rufomycin. Although these molecules are promising starting points for drug development, their mechanisms of action remain largely unknown. Taking advantage of a middle domain mutant, we determined the first structure of Mycobacterium tuberculosis ClpC1 in its apo, cyclomarin-, and ecumicin-bound states via cryo-EM. The obtained structure displays features observed in other members of the AAA+ family and provides a map for further drug development. While the apo and cyclomarin-bound structures are indistinguishable and have N-terminal domains that are invisible in their respective EM maps, around half of the ecumicin-bound ClpC1 particles display three of their six N-terminal domains in an extended conformation. Our structural observations suggest a mechanism where ecumicin functions by mimicking substrate binding, leading to ATPase activation and changes in protein degradation profile. Structure of the drug target ClpC1 unfoldase in action provides insights on antibiotic mechanism of action.,Weinhaupl K, Gragera M, Bueno-Carrasco MT, Arranz R, Krandor O, Akopian T, Soares R, Rubin E, Felix J, Fraga H J Biol Chem. 2022 Nov;298(11):102553. doi: 10.1016/j.jbc.2022.102553. Epub 2022 , Oct 6. PMID:36208775 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Clp protease 3D structures

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