2a3c
From Proteopedia
Crystal structure of Aspergillus fumigatus chitinase B1 in complex with pentoxifylline
Structural highlights
FunctionCHIB1_ASPFM Major secreted 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). Plays a role in the morphogenesis and autolysis (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFamily 18 chitinases play key roles in a range of pathogenic organisms and are overexpressed in the asthmatic lung. By screening a library of marketed drug molecules, we have identified methylxanthine derivatives as possible inhibitor leads. These derivatives, theophylline, caffeine, and pentoxifylline, are used therapeutically as antiinflammatory agents, with pleiotropic mechanisms of action. Here it is shown that they are also competitive inhibitors against a fungal family 18 chitinase, with pentoxifylline being the most potent (K(i) of 37 microM). Crystallographic analysis of chitinase-inhibitor complexes revealed specific interactions with the active site, mimicking the reaction intermediate analog, allosamidin. Mutagenesis identified the key active site residues, conserved in mammalian chitinases, which contribute to inhibitor affinity. Enzyme assays also revealed that these methylxanthines are active against human chitinases. Methylxanthine drugs are chitinase inhibitors: investigation of inhibition and binding modes.,Rao FV, Andersen OA, Vora KA, Demartino JA, van Aalten DM Chem Biol. 2005 Sep;12(9):973-80. PMID:16183021[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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