4ADW

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

Summary for 4ADW

• Entry DOI: 10.2210/pdb4adw/pdb
• Related: 2JK6 2W0H 2X50 2YAU
• Descriptor: TRYPANOTHIONE REDUCTASE, FLAVIN-ADENINE DINUCLEOTIDE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: oxidoreductase, inhibition mechanism
• Biological source: LEISHMANIA INFANTUM
• Total number of polymer chains: 2
• Total formula weight: 115024.76

Authors

Baiocco, P.,Ilari, A.,Colotti, G.,Malatesta, F.,Fiorillo, A. (deposition date: 2012-01-04, release date: 2013-01-16, Last modification date: 2023-12-20)

Primary citation

Baiocco, P.,Poce, G.,Alfonso, S.,Cocozza, M.,Porretta, G.C.,Colotti, G.,Biava, M.,Moraca, F.,Botta, M.,Yardley, V.,Fiorillo, A.,Lantella, A.,Malatesta, F.,Ilari, A.
Inhibition of Leishmania Infantum Trypanothione Reductase by Azole-Based Compounds: A Comparative Analysis with its Physiological Substrate by X-Ray Crystallography.
Chemmedchem, 8:1175-, 2013

PubMed Abstract: 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)thiomorpholine (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.

PubMed: 23733388
DOI: 10.1002/CMDC.201300176

Experimental method

X-RAY DIFFRACTION (3.61 Å)