PDBsum entry 2w0h

Oxidoreductase

PDB id: 2w0h

Contents

Protein chains

485 a.a. *

Ligands

FAD ×2

NDP ×2

SO4 ×2

Metals

_SB ×2

Waters ×26

* Residue conservation analysis

PDB id:

2w0h

Name:

Oxidoreductase

Title:

X ray structure of leishmania infantum trypanothione reductase in complex with antimony and NADPH

Structure:

Trypanothione reductase. Chain: a, b. Engineered: yes

Source:

Leishmania infantum. Organism_taxid: 5671. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

3.00Å R-factor: 0.239 R-free: 0.262

Authors:

P.Baiocco,G.Colotti,S.Franceschini,A.Ilari

Key ref:

P.Baiocco et al. (2009). Molecular basis of antimony treatment in leishmaniasis. J Med Chem, 52, 2603-2612. PubMed id: 19317451

Date:

18-Aug-08 Release date: 28-Apr-09

Protein chains

A4HSF7  (A4HSF7_LEIIN) -  Trypanothione reductase from Leishmania infantum

Seq: 491 a.a.

Struc: 485 a.a.

Enzyme reactions

• Enzyme class: E.C.1.8.1.12 - trypanothione-disulfide reductase.
• Reaction: trypanothione + NADP⁺ = trypanothione disulfide + NADPH + H⁺

trypanothione (Bound ligand (Het Group name = NDP) corresponds exactly) + NADP(+) = trypanothione disulfide + NADPH + H(+)

• Cofactor: FAD

FAD (Bound ligand (Het Group name = FAD) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 52:2603-2612 (2009)

PubMed id: 19317451

Molecular basis of antimony treatment in leishmaniasis.

P.Baiocco, G.Colotti, S.Franceschini, A.Ilari.

ABSTRACT

Leishmaniasis is a disease that affects 2 million people and kills 70000 persons every year. It is caused by Leishmania species, which are human protozoan parasites of the trypanosomatidae family. Trypanosomatidae differ from the other eukaryotes in their specific redox metabolism because the glutathione/glutathione reductase system is replaced by the unique trypanothione/trypanothione reductase system. The current treatment of leishmaniasis relies mainly on antimonial drugs. The crystal structures of oxidized trypanothione reductase (TR) from Leishmania infantum and of the complex of reduced TR with NADPH and Sb(III), reported in this paper, disclose for the first time the molecular mechanism of action of antimonial drugs against the parasite. Sb(III), which is coordinated by the two redox-active catalytic cysteine residues (Cys52 and Cys57), one threonine residue (Thr335), and His461' of the 2-fold symmetry related subunit in the dimer, strongly inhibits TR activity. Because TR is essential for the parasite survival and virulence and it is absent in mammalian cells, these findings provide insights toward the design of new more affordable and less toxic drugs against Leishmaniasis.