3wdc

N-terminal domain of Mycobacterium tuberculosis ClpC1 bound to Cyclomarin A

spinqualitylabelsall models 3wdc, resolution 1.18Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3wdc is a 2 chain structure with sequence from Mycobacterium tuberculosis and Streptomyces sp.. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.18Å Ligands: ACT, MLE, WLU, WPA, WRP, WVL 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 Cyclomarin A (CymA) was identified as a mycobactericidal compound targeting ClpC1. However, the target was identified based on pulldown experiments and in vitro binding data, without direct functional evidence in mycobacteria. Here we show that CymA specifically binds to the N-terminal domain of ClpC1. In addition we have determined the co-crystal structure of CymA bound to the N-terminal domain of ClpC1 to high resolution. Based on the structure of the complex several mutations were engineered into ClpC1, which showed reduced CymA binding in vitro. The ClpC1 mutants were overexpressed in mycobacteria and two showed resistance to CymA, providing the first direct evidence that ClpC1 is the target of CymA. Phe(80) is important in vitro and in cells for the ClpC1-CymA interaction and this explains why other bacteria are resistant to CymA. A model for how CymA binding to the N-terminal domain of ClpC1 leads to uncontrolled proteolysis by the associated ClpP protease machinery is discussed. Structural basis of mycobacterial inhibition by cyclomarin A.,Vasudevan D, Rao SP, Noble CG J Biol Chem. 2013 Oct 25;288(43):30883-91. doi: 10.1074/jbc.M113.493767. Epub, 2013 Sep 10. PMID:24022489 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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