2xuc

Natural product-guided discovery of a fungal chitinase inhibitorNatural product-guided discovery of a fungal chitinase inhibitor

Structural highlights 2xuc is a 3 chain structure with sequence from Aspergillus fumigatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CHIA1_ASPFM GPI-anchored chitinase involved in the degradation of chitin, a component of the cell walls of fungi and exoskeletal elements of some animals (including worms and arthropods). Required to reshape the cell wall at the sites where cell wall remodeling and/or cell wall maturation actively take place such as sites of conidia formation. Publication Abstract from PubMed Natural products are often large, synthetically intractable molecules, yet frequently offer surprising inroads into previously unexplored chemical space for enzyme inhibitors. Argifin is a cyclic pentapeptide that was originally isolated as a fungal natural product. It competitively inhibits family 18 chitinases by mimicking the chitooligosaccharide substrate of these enzymes. Interestingly, argifin is a nanomolar inhibitor of the bacterial-type subfamily of fungal chitinases that possess an extensive chitin-binding groove, but does not inhibit the much smaller, plant-type enzymes from the same family that are involved in fungal cell division and are thought to be potential drug targets. Here we show that a small, highly efficient, argifin-derived, nine-atom fragment is a micromolar inhibitor of the plant-type chitinase ChiA1 from the opportunistic pathogen Aspergillus fumigatus. Evaluation of the binding mode with the first crystal structure of an A. fumigatus plant-type chitinase reveals that the compound binds the catalytic machinery in the same manner as observed for argifin with the bacterial-type chitinases. The structure of the complex was used to guide synthesis of derivatives to explore a pocket near the catalytic machinery. This work provides synthetically tractable plant-type family 18 chitinase inhibitors from the repurposing of a natural product. Natural product-guided discovery of a fungal chitinase inhibitor.,Rush CL, Schuttelkopf AW, Hurtado-Guerrero R, Blair DE, Ibrahim AF, Desvergnes S, Eggleston IM, van Aalten DM Chem Biol. 2010 Dec 22;17(12):1275-81. PMID:21168763 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Chitinase 3D structures

spinqualitylabelsall models 2xuc, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image