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  • 1
    Language: English
    In: The Journal of biological chemistry, 15 October 2010, Vol.285(42), pp.32557-67
    Description: Schistosomiasis is the second most widespread human parasitic disease. It is principally treated with one drug, praziquantel, that is administered to 100 million people each year; less sensitive strains of schistosomes are emerging. One of the most appealing drug targets against schistosomiasis is thioredoxin glutathione reductase (TGR). This natural chimeric enzyme is a peculiar fusion of a glutaredoxin domain with a thioredoxin selenocysteine (U)-containing reductase domain. Selenocysteine is located on a flexible C-terminal arm that is usually disordered in the available structures of the protein and is essential for the full catalytic activity of TGR. In this study, we dissect the catalytic cycle of Schistosoma mansoni TGR by structural and functional analysis of the U597C mutant. The crystallographic data presented herein include the following: the oxidized form (at 1.9 Å resolution); the NADPH- and GSH-bound forms (2.3 and 1.9 Å, respectively); and a different crystal form of the (partially) reduced enzyme (3.1 Å), showing the physiological dimer and the entire C terminus of one subunit. Whenever possible, we determined the rate constants for the interconversion between the different oxidation states of TGR by kinetic methods. By combining the crystallographic analysis with computer modeling, we were able to throw further light on the mechanism of action of S. mansoni TGR. In particular, we hereby propose the putative functionally relevant conformational change of the C terminus after the transfer of reducing equivalents from NADPH to the redox sites of the enzyme.
    Keywords: Protein Structure, Tertiary ; Crystallography, X-Ray -- Methods ; Multienzyme Complexes -- Chemistry ; Nadh, Nadph Oxidoreductases -- Chemistry ; Schistosoma Mansoni -- Enzymology
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 2
    Language: English
    In: Biochemical and Biophysical Research Communications, 07 September 2012, Vol.425(4), pp.806-811
    Description: ► The thioredoxin system is crucial to the viability of . ► The system is headed by NADPH-dependent thioredoxin reductase (PfTrxR). ► We present the first crystal structure of PfTrxR, a validated drug target. ► The interface and the central cavity are different from the human counterpart. ► These differences could be exploited for future rational inhibitors design. is the vector of the most prevalent and deadly form of malaria, and, among the species, it is the one with the highest rate of drug resistance. At the basis of a rational drug design project there is the selection and characterization of suitable target(s). Thioredoxin reductase, the first protection against reactive oxygen species in the erythrocytic phase of the parasite, is essential for its survival. Hence it represents a good target for the design of new anti-malarial active compounds. In this paper we present the first crystal structure of recombinant thioredoxin reductase (PfTrxR) at 2.9 Å and discuss its differences with respect to the human orthologue. The most important one resides in the dimer interface, which offers a good binding site for selective non competitive inhibitors. The striking conservation of this feature among the parasites, but not among other Apicomplexa parasites neither in mammals, boosts its exploitability.
    Keywords: Malaria ; Thiol-Mediated Redox Metabolism ; Thioredoxin Reductase ; Protein Crystallography ; Rational Drug Design ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 3
    Language: English
    In: Current Topics in Medicinal Chemistry, 2011, Vol.11(16), p.2012-2028
    Description: Schistosomiasis is a widespread tropical parasitic disease, currently treated with Praziquantel, whose precise molecular target is actually unknown. Several other drugs are known to kill the schistosomes in vivo and in vitro, but these are seldom employed because of toxicity, high cost, complex administration or other reasons. The improvement of known drugs or the development of entirely new ones is a desirable goal, in view of the fact that strains of Schistosoma mansoni with reduced sensitivity to Praziquantel have appeared. In this review, we tried to collect the information available on known or putative macromolecular targets of schistosomicidal drugs; thus we focused on the biochemistry of the parasite, rather than the clinical properties of the drugs. The rationale of this approach is that drug design may become realistic if the mechanism of action of each known drug were known at atomic detail, ideally as the 3D structure of each drug in complex with its target. Important macromolecular targets of known drugs reviewed below are: Thioredoxin Glutathione Reductase; Cyclophilin; Acetyl Cholinesterase; Proteases and Purine Nucleoside Phosphorylase. Moreover, a few enzymes of the parasite are known, or thought, to be “druggable”, and therefore interesting, even though no specific drugs are available as yet: examples of such enzymes are Glutathione Peroxidase and Peroxiredoxins.
    Keywords: Artemisinin ; Auranofin ; Neglected Tropical Disease ; Oxamniquine ; Praziquantel ; Proteases ; Thioredoxin Glutathione Reductase ; Schistosomiasis ; Crystal Structure ; Schistosomes ; Toxicity ; Cyclophilin ; Acetyl Cholinesterase ; Druggable
    ISSN: 1568-0266
    E-ISSN: 1873-5294
    E-ISSN: 18734294
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  • 4
    Language: English
    In: Protein Science, June 2011, Vol.20(6), pp.1069-1076
    Description: Schistosomiasis, the human parasitosis caused by various species of the blood‐fluke , is a debilitating disease affecting 200 million people in tropical areas. The massive administration of the only effective drug, praziquantel, leads to the appearance of less sensitive parasite strains, thus, making urgent the search for new therapeutic approaches and new suitable targets. The thiol‐mediated detoxification pathway has been identified as a promising target, being essential during all the parasite developmental stages and sufficiently different from the host counterpart. As a part of a project aimed at the structural characterization of all the proteins involved in this pathway, we describe hereby the high‐resolution crystal structure of Thioredoxin (SmTrx) in three states, namely: the wild‐type oxidized adult enzyme and the oxidized and reduced forms of a juvenile isoform, carrying an N‐terminal extension. SmTrx shows a typical thioredoxin fold, highly similar to the other components of the superfamily. Although probably unlikely to be a reasonable drug target given its high similarity with the human counterpart, SmTrx completes the characterization of the whole set of thiol‐mediated detoxification pathway components. Moreover, it can reduce oxidized glutathione and is one of the few defence proteins expressed in mature eggs and in the hatch fluid, thus confirming an important role in the parasite. We believe its crystal structure may provide clues for the formation of granulomas and the pathogenesis of the chronic disease. , | PDB Code(s): , , ,
    Keywords: Schistosomiasis ; Structural Genomics ; X‐Ray Crystallography ; Thioredoxin ; Detoxification Metabolism
    ISSN: 0961-8368
    E-ISSN: 1469-896X
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  • 5
    Language: English
    In: Nucleic acids research, 01 November 2012, Vol.40(20), pp.10417-31
    Description: The RNA degradosome is a multi-enzyme assembly that contributes to key processes of RNA metabolism, and it engages numerous partners in serving its varied functional roles. Small domains within the assembly recognize collectively a diverse range of macromolecules, including the core protein components, the cytoplasmic lipid membrane, mRNAs, non-coding regulatory RNAs and precursors of structured RNAs. We present evidence that the degradosome can form a stable complex with the 70S ribosome and polysomes, and we demonstrate the proximity in vivo of ribosomal proteins and the scaffold of the degradosome, RNase E. The principal interactions are mapped to two, independent, RNA-binding domains from RNase E. RhlB, the RNA helicase component of the degradosome, also contributes to ribosome binding, and this is favoured through an activating interaction with RNase E. The catalytic activity of RNase E for processing 9S RNA (the ribosomal 5S RNA precursor) is repressed in the presence of the ribosome, whereas there is little affect on the cleavage of single-stranded substrates mediated by non-coding RNA, suggestings that the enzyme retains capacity to cleave unstructured substrates when associated with the ribosome. We propose that polysomes may act as antennae that enhance the rates of capture of the limited number of degradosomes, so that they become recruited to sites of active translation to act on mRNAs as they become exposed or tagged for degradation.
    Keywords: Endoribonucleases -- Metabolism ; Escherichia Coli -- Enzymology ; Multienzyme Complexes -- Metabolism ; Polyribonucleotide Nucleotidyltransferase -- Metabolism ; Polyribosomes -- Metabolism ; RNA Helicases -- Metabolism ; Ribosomes -- Metabolism
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 6
    Language: English
    In: eLife, 31 December 2014, Vol.3
    Description: Bacterial small RNAs (sRNAs) are key elements of regulatory networks that modulate gene expression. The sRNA RydC of Salmonella sp. and Escherichia coli is an example of this class of riboregulators. Like many other sRNAs, RydC bears a 'seed' region that recognises specific transcripts through base-pairing, and its activities are facilitated by the RNA chaperone Hfq. The crystal structure of RydC in complex with E. coli Hfq at a 3.48 Å resolution illuminates how the protein interacts with and presents the sRNA for target recognition. Consolidating the protein-RNA complex is a host of distributed interactions mediated by the natively unstructured termini of Hfq. Based on the structure and other data, we propose a model for a dynamic effector complex comprising Hfq, small RNA, and the cognate mRNA target.
    Keywords: E. Coli ; Hfq ; RNA–Protein Interactions ; Rydc ; Biophysics ; Gene Regulation ; Natively Unstructured Protein ; Srna ; Structural Biology ; Host Factor 1 Protein -- Metabolism ; RNA, Bacterial -- Metabolism
    E-ISSN: 2050-084X
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  • 7
    Language: English
    In: The Journal of biological chemistry, 16 October 2009, Vol.284(42), pp.28977-85
    Description: Schistosomiasis is a parasitic disease affecting over 200 million people currently treated with one drug, praziquantel. A possible drug target is the seleno-protein thioredoxin-glutathione reductase (TGR), a key enzyme in the pathway of the parasite for detoxification of reactive oxygen species. The enzyme is a unique fusion of a glutaredoxin domain with a thioredoxin reductase domain, which contains a selenocysteine (Sec) as the penultimate amino acid. Auranofin (AF), a gold-containing compound already in clinical use as an anti-arthritic drug, has been shown to inhibit TGR and to substantially reduce worm burden in mice. Using x-ray crystallography we solved (at 2.5 A resolution) the structure of wild type TGR incubated with AF. The electron density maps show that the actual inhibitor is gold, released from AF. Gold is bound at three different sites not directly involving the C-terminal Sec residue; however, because the C terminus in the electron density maps is disordered, we cannot exclude the possibility that gold may also bind to Sec. To investigate the possible role of Sec in the inactivation kinetics, we tested the effect of AF on a model enzyme of the same superfamily, i.e. the naturally Sec-lacking glutathione reductase, and on truncated TGR. We demonstrate that the role of selenium in the onset of inhibition by AF is catalytic and can be mimicked by an external source of selenium (benzeneselenol). Therefore, we propose that Sec mediates the transfer of gold from its ligands in AF to the redox-active Cys couples of TGR.
    Keywords: Gene Expression Regulation ; Antirheumatic Agents -- Chemistry ; Auranofin -- Chemistry ; Helminth Proteins -- Chemistry ; Multienzyme Complexes -- Chemistry ; Nadh, Nadph Oxidoreductases -- Chemistry ; Schistosoma Mansoni -- Metabolism
    ISSN: 00219258
    E-ISSN: 1083-351X
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  • 8
    Language: English
    In: Proteins: Structure, Function, and Bioinformatics, 01 February 2010, Vol.78(2), pp.259-270
    Description: Oxidative stress is a widespread challenge for living organisms, and especially so for parasitic ones, given the fact that their hosts can produce reactive oxygen species (ROS) as a mechanism of defense. Thus, long lived parasites, such as the flatworm Schistosomes, have evolved refined enzymatic systems capable of detoxifying ROS. Among these, glutathione peroxidases (Gpx) are a family of sulfur or selenium‐dependent isozymes sharing the ability to reduce peroxides using the reducing equivalents provided by glutathione or possibly small proteins such as thioredoxin. As for other frontline antioxidant enzymatic systems, Gpxs are localized in the tegument of the Schistosomes, the outermost defense layer. In this article, we present the first crystal structure at 1.0 and 1.7 Å resolution of two recombinant SmGpxs, carrying the active site mutations Sec43Cys and Sec43Ser, respectively. The structures confirm that this enzyme belongs to the monomeric class 4 (phospholipid hydroperoxide) Gpx. In the case of the Sec to Cys mutant, the catalytic Cys residue is oxidized to sulfonic acid. By combining static crystallography with molecular dynamics simulations, we obtained insight into the substrate binding sites and the conformational changes relevant to catalysis, proposing a role for the unusual reactivity of the catalytic residue. Proteins 2010. © 2009 Wiley‐Liss, Inc.
    Keywords: Atomic Resolution Crystal Structure ; Ros Detoxification Pathway ; Schistosomiasis ; Lipid Gsh Peroxidase ; Molecular Dynamics Simulations
    ISSN: 0887-3585
    E-ISSN: 1097-0134
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  • 9
    Language: English
    In: Proteins: Structure, Function, and Bioinformatics, 15 August 2008, Vol.72(3), pp.936-945
    Description: Thioredoxin glutathione reductase (TGR) is a key flavoenzyme expressed by schistosomes that bridges two detoxification pathways crucial for the parasite survival in the host's organism. In this article we report the crystal structure (at 2.2 Å resolution) of TGR from (SmTGR), deleted in the last two residues. The structure reveals the peculiar architecture of this chimeric enzyme: the small Glutaredoxin (Grx) domain at the N‐terminus is joined to the large thioredoxin reductase (TR) one via an extended complementary surface, involving residues not conserved in the Grx superfamily; the TR domain interacts with an identical partner via its C‐terminal domain, forming a dimer with a twisted “W” shape. Although lacking the penultimate Selenocysteine residue (Sec), the enzyme is still able to reduce oxidized glutathione. These data update the interpretation of the interdomain communication in TGR enzymes. The possible function of this enzyme in pathogenic parasites is discussed. Proteins 2008. © 2008 Wiley‐Liss, Inc.
    Keywords: Schistosomiasis ; Redox‐Detoxification Pathway ; Structure‐Based Drug Design ; Supramolecular Assembly ; Glutaredoxin ; Thioredoxin Reductase
    ISSN: 0887-3585
    E-ISSN: 1097-0134
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  • 10
    Description: This paper discusses the science case for a sensitive spectro-polarimetric survey of the microwave sky. Such a survey would provide a tomographic and dynamic census of the three-dimensional distribution of hot gas, velocity flows, early metals, dust, and mass distribution in the entire Hubble volume, exploit CMB temperature and polarisation anisotropies down to fundamental limits, and track energy injection and absorption into the radiation background across cosmic times by measuring spectral distortions of the CMB blackbody emission. In addition to its exceptional capability for cosmology and fundamental physics, such a survey would provide an unprecedented view of microwave emissions at sub-arcminute to few-arcminute angular resolution in hundreds of frequency channels, a data set that would be of immense legacy value for many branches of astrophysics. We propose that this survey be carried-out with a large space mission featuring a broad-band polarised imager and a moderate resolution spectro-imager at the focus of a 3.5m aperture telescope actively cooled to about 8K, complemented with absolutely-calibrated Fourier Transform Spectrometer modules observing at degree-scale angular resolution in the 10-2000 GHz frequency range. We propose two observing modes: a survey mode to map the entire sky as well as a few selected wide fields, and an observatory mode for deeper observations of regions of specific interest. Comment: 20 pages, white paper submitted in answer to the "Voyage 2050" call to prepare the long term plan in the ESA science programme
    Keywords: Astrophysics - Cosmology And Nongalactic Astrophysics ; Astrophysics - Astrophysics Of Galaxies ; Astrophysics - Instrumentation And Methods For Astrophysics ; General Relativity And Quantum Cosmology
    Source: Cornell University
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