2wpe

Trypanosoma brucei trypanothione reductase in complex with 3,4- dihydroquinazoline inhibitor (DDD00073359)

spinqualitylabelsall models 2wpe, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2wpe is a 4 chain structure with sequence from Trypanosoma brucei brucei TREU927. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Ligands: CL, FAD, MPD, MRD, NA, WPE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q389T8_TRYB2 Publication Abstract from PubMed Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay. Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography.,Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA, Wyatt PG, Gilbert IH, Fairlamb AH J Med Chem. 2011 Oct 13;54(19):6514-30. Epub 2011 Sep 1. PMID:21851087 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Trypanothione reductase

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