2JK6

Structure of Trypanothione Reductase from Leishmania infantum

Summary for 2JK6

• Entry DOI: 10.2210/pdb2jk6/pdb
• Related: 2W0H
• Descriptor: TRYPANOTHIONE REDUCTASE, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: oxidant detoxification, trypanothione metabolism, fad, leishmania, trypanosoma, antimonials, flavoprotein, oxidoreductase, redox-active center
• Biological source: LEISHMANIA INFANTUM
• Total number of polymer chains: 2
• Total formula weight: 112566.51

Authors

Baiocco, P.,Colotti, G.,Franceschini, S.,Ilari, A. (deposition date: 2008-08-21, release date: 2009-04-28, Last modification date: 2024-10-23)

Primary citation

Baiocco, P.,Colotti, G.,Franceschini, S.,Ilari, A.
Molecular Basis of Antimony Treatment in Leishmaniasis.
J.Med.Chem., 52:2603-, 2009

PubMed 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.

PubMed: 19317451
DOI: 10.1021/JM900185Q

Experimental method

X-RAY DIFFRACTION (2.95 Å)