2xvn

A. FUMIGATUS CHITINASE A1 PHENYL-METHYLGUANYLUREA COMPLEX

spinqualitylabelsall models 2xvn, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2xvn 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. Ligands: CL, KLS Related: 2xuc, 2xvp Resources: FirstGlance, OCA, RCSB, PDBsum 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

Proteopedia Page Contributors and Editors (what is this?)

OCA