4ADW: Crystal Structure Of Leishmania Infantum Trypanothione Reductase In Complex With Nadph And Trypanothione

Citation:
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.
PDB ID: 4ADWDownload
MMDB ID: 106646
PDB Deposition Date: 2012/1/4
Updated in MMDB: 2013/07
Experimental Method:
x-ray diffraction
Resolution: 3.61  Å
Source Organism:
Similar Structures:
Biological Unit for 4ADW: dimeric; determined by author and by software (PISA)
Molecular Components in 4ADW
Label Count Molecule
Proteins (2 molecules)
2
Trypanothione Reductase
Molecule annotation
Chemicals (6 molecules)
1
2
2
2
3
2
* Click molecule labels to explore molecular sequence information.

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