1bzl

CRYSTAL STRUCTURE OF TRYPANOSOMA CRUZI TRYPANOTHIONE REDUCTASE IN COMPLEX WITH TRYPANOTHIONE, AND THE STRUCTURE-BASED DISCOVERY OF NEW NATURAL PRODUCT INHIBITORS

spinqualitylabelsall models 1bzl, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1bzl is a 2 chain structure with sequence from Trypanosoma cruzi. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: FAD, GCG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TYTR_TRYCR Trypanothione is the parasite analog of glutathione; this enzyme is the equivalent of glutathione reductase. 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 PubMed BACKGROUND: Trypanothione reductase (TR) helps to maintain an intracellular reducing environment in trypanosomatids, a group of protozoan parasites that afflict humans and livestock in tropical areas. This protective function is achieved via reduction of polyamine-glutathione conjugates, in particular trypanothione. TR has been validated as a chemotherapeutic target by molecular genetics methods. To assist the development of new therapeutics, we have characterised the structure of TR from the pathogen Trypanosoma cruzi complexed with the substrate trypanothione and have used the structure to guide database searches and molecular modelling studies. RESULTS: The TR-trypanothione-disulfide structure has been determined to 2.4 A resolution. The chemical interactions involved in enzyme recognition and binding of substrate can be inferred from this structure. Comparisons with the related mammalian enzyme, glutathione reductase, explain why each enzyme is so specific for its own substrate. A CH***O hydrogen bond can occur between the active-site histidine and a carbonyl of the substrate. This interaction contributes to enzyme specificity and mechanism by producing an electronic induced fit when substrate binds. Database searches and molecular modelling using the substrate as a template and the active site as receptor have identified a class of cyclic-polyamine natural products that are novel TR inhibitors. CONCLUSIONS: The structure of the TR-trypanothione enzyme-substrate complex provides details of a potentially valuable drug target. This information has helped to identify a new class of enzyme inhibitors as novel lead compounds worthy of further development in the search for improved medicines to treat a range of parasitic infections. Crystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors.,Bond CS, Zhang Y, Berriman M, Cunningham ML, Fairlamb AH, Hunter WN Structure. 1999 Jan 15;7(1):81-9. PMID:10368274 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Trypanothione reductase

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