4adw

CRYSTAL STRUCTURE OF LEISHMANIA INFANTUM TRYPANOTHIONE REDUCTASE IN COMPLEX WITH NADPH AND TRYPANOTHIONE

spinqualitylabelsall models 4adw, resolution 3.61Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4adw is a 2 chain structure with sequence from Leiin. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FAD, GCG, NDP Related: 2jk6, 2w0h, 2x50, 2yau Activity: Trypanothione-disulfide reductase, with EC number 1.8.1.12 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Herein we report a study aimed at discovering a new class of compounds that are able to inhibit Leishmania donovani cell growth. Evaluation of an in-house library of compounds in a whole-cell screening assay highlighted 4-((1-(4-ethylphenyl)-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3-yl)methyl)thi omorpholine (compound 1) as the most active. Enzymatic assays on Leishmania infantum trypanothione reductase (LiTR, belonging to the Leishmania donovani complex) shed light on both the interaction with, and the nature of inhibition by, compound 1. A molecular modeling approach based on docking studies and on the estimation of the binding free energy aided our rationalization of the biological data. Moreover, X-ray crystal structure determination of LiTR in complex with compound 1 confirmed all our results: compound 1 binds to the T(SH)2 binding site, lined by hydrophobic residues such as Trp21 and Met113, as well as residues Glu18 and Tyr110. Analysis of the structure of LiTR in complex with trypanothione shows that Glu18 and Tyr110 are also involved in substrate binding, according to a competitive inhibition mechanism. Inhibition of Leishmania infantum Trypanothione Reductase by Azole-Based Compounds: a Comparative Analysis with Its Physiological Substrate by X-ray Crystallography.,Baiocco P, Poce G, Alfonso S, Cocozza M, Porretta GC, Colotti G, Biava M, Moraca F, Botta M, Yardley V, Fiorillo A, Lantella A, Malatesta F, Ilari A ChemMedChem. 2013 Jun 3. doi: 10.1002/cmdc.201300176. PMID:23733388 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Trypanothione reductase

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