2oma

Crystallographic analysis of a chemically modified triosephosphate isomerase from Trypanosoma cruzi with dithiobenzylamine (DTBA)

spinqualitylabelsall models 2oma, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2oma is a 2 chain structure with sequence from Trycr. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: PEG, PGE, SO4 NonStd Res: CS1 Related: 1tcd Activity: Triose-phosphate isomerase, with EC number 5.3.1.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed BACKGROUND: Chagas disease affects around 18 million people in the American continent. Unfortunately, there is no satisfactory treatment for the disease. The drugs currently used are not specific and exert serious toxic effects. Thus, there is an urgent need for drugs that are effective. Looking for molecules to eliminate the parasite, we have targeted a central enzyme of the glycolytic pathway: triosephosphate isomerase (TIM). The homodimeric enzyme is catalytically active only as a dimer. Because there are significant differences in the interface of the enzymes from the parasite and humans, we searched for small molecules that specifically disrupt contact between the two subunits of the enzyme from Trypanosoma cruzi but not those of TIM from Homo sapiens (HTIM), and tested if they kill the parasite. METHODOLOGY/PRINCIPAL FINDINGS: Dithiodianiline (DTDA) at nanomolar concentrations completely inactivates recombinant TIM of T. cruzi (TcTIM). It also inactivated HTIM, but at concentrations around 400 times higher. DTDA was also tested on four TcTIM mutants with each of its four cysteines replaced with either valine or alanine. The sensitivity of the mutants to DTDA was markedly similar to that of the wild type. The crystal structure of the TcTIM soaked in DTDA at 2.15 A resolution, and the data on the mutants showed that inactivation resulted from alterations of the dimer interface. DTDA also prevented the growth of Escherichia coli cells transformed with TcTIM, had no effect on normal E. coli, and also killed T. cruzi epimastigotes in culture. CONCLUSIONS/SIGNIFICANCE: By targeting on the dimer interface of oligomeric enzymes from parasites, it is possible to discover small molecules that selectively thwart the life of the parasite. Also, the conformational changes that DTDA induces in the dimer interface of the trypanosomal enzyme are unique and identify a region of the interface that could be targeted for drug discovery. Perturbation of the Dimer Interface of Triosephosphate Isomerase and its Effect on Trypanosoma cruzi.,Olivares-Illana V, Rodriguez-Romero A, Becker I, Berzunza M, Garcia J, Perez-Montfort R, Cabrera N, Lopez-Calahorra F, de Gomez-Puyou MT, Gomez-Puyou A PLoS Negl Trop Dis. 2007 Oct 31;1(1):e1. PMID:17989778 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Triose Phosphate Isomerase

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