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PDBsum entry 2w0h
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Oxidoreductase
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PDB id
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2w0h
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References listed in PDB file
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Key reference
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Title
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Molecular basis of antimony treatment in leishmaniasis.
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Authors
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P.Baiocco,
G.Colotti,
S.Franceschini,
A.Ilari.
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Ref.
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J Med Chem, 2009,
52,
2603-2612.
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PubMed id
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Abstract
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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.
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