2ybu
Crystal structure of human acidic chitinase in complex with bisdionin F
Structural highlights
FunctionCHIA_HUMAN Degrades chitin and chitotriose. May participate in the defense against nematodes, fungi and other pathogens. Plays a role in T-helper cell type 2 (Th2) immune response. Contributes to the response to IL-13 and inflammation in response to IL-13. Stimulates chemokine production by pulmonary epithelial cells. Protects lung epithelial cells against apoptosis and promotes phosphorylation of AKT1. Its function in the inflammatory response and in protecting cells against apoptosis is inhibited by allosamidin, suggesting that the function of this protein depends on carbohydrate binding.[1] [2] [3] [4] Publication Abstract from PubMedAcidic mammalian chitinase (AMCase) is produced in the lung during allergic inflammation and asthma, and inhibition of enzymatic activity has been considered as a therapeutic strategy. However, most chitinase inhibitors are nonselective, additionally inhibiting chitotriosidase activity. Here, we describe bisdionin F, a competitive AMCase inhibitor with 20-fold selectivity for AMCase over chitotriosidase, designed by utilizing the AMCase crystal structure and dicaffeine scaffold. In a murine model of allergic inflammation, bisdionin F-treatment attenuated chitinase activity and alleviated the primary features of allergic inflammation including eosinophilia. However, selective AMCase inhibition by bisdionin F also caused dramatic and unexpected neutrophilia in the lungs. This class of inhibitor will be a powerful tool to dissect the functions of mammalian chitinases in disease and represents a synthetically accessible scaffold to optimize inhibitory properties in terms of airway inflammation. Analyzing Airway Inflammation with Chemical Biology: Dissection of Acidic Mammalian Chitinase Function with a Selective Drug-like Inhibitor.,Sutherland TE, Andersen OA, Betou M, Eggleston IM, Maizels RM, van Aalten D, Allen JE Chem Biol. 2011 May 27;18(5):569-79. PMID:21609838[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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