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Gopinatha Suresh Kumar - One of the best experts on this subject based on the ideXlab platform.

  • small molecule rna recognition binding of the benzophenanthridine alkaloids sanguinarine and chelerythrine to single stranded Polyribonucleotides
    Journal of Photochemistry and Photobiology B-biology, 2017
    Co-Authors: Pritha Basu, Gopinatha Suresh Kumar
    Abstract:

    Abstract Single stranded RNAs are biologically potent as they participate in various key cellular processes. The binding efficacy of two potent anticancer alkaloids, sanguinarine (here after SANG) and chelerythrine (here after CHEL), with single-stranded ribonucleic acids poly(rI), poly(rG), and poly(rC) were studied using spectroscopic and thermodynamic tools. Results reveal that both SANG and CHEL binds well with single stranded RNAs with affinity in the order poly(rI) > poly(rG) > poly(rC). CHEL showed slightly higher affinity compared to SANG with all the single stranded RNAs. Both SANG and CHEL showed association affinity of the lower 10 6 order with poly(rI), higher 10 5 order binding with poly(rG) and lower 10 5 order with poly(rC). The binding mode was partial intercalation due to the staking interaction between the bases and the alkaloids. The complexation of both the SANG and CHEL to the RNAs were mainly enthalpy driven and also favoured by entropy changes. Perturbation was observed in the RNA conformation due to binding of the alkaloids. In this present study we have deciphered the fundamental structural and calorimetric aspects of the interaction of the natural benzophenanthridine alkaloids with single stranded RNAs and these results may help to develop new generation alkaloid based therapeutics targeting single stranded RNAs.

  • rna binding potential of protoberberine alkaloids spectroscopic and calorimetric studies on the binding of berberine palmatine and coralyne to protonated rna structures
    DNA and Cell Biology, 2009
    Co-Authors: Md Maidul Islam, Gopinatha Suresh Kumar
    Abstract:

    Interaction of the protoberberine alkaloids berberine, palmatine, and coralyne with the two double-stranded RNA homopolymers of cytidine-guanosine (CG) and inosine-cytidine (IC) sequences in the protonated conformation was investigated using various biophysical techniques. All the three alkaloids bound polyC(+)G in a cooperative way. The binding of coralyne to both the Polyribonucleotides was stronger than that of berberine and palmatine. Evidence for the intercalative binding of coralyne was revealed from fluorescence quenching studies. Isothermal titration calorimetry results suggested that the binding of berberine to both the polymers and palmatine to polyIC(+) was very weak while that of palmatine and coralyne to polyC(+)G and polyIC(+) was predominantly entropy driven. Circular dichroic results provided evidence for the perturbation of the RNA conformation with the bound coralyne in a more deeply intercalated position compared to berberine and palmatine as revealed by induced circular dichroism peaks. Taken together, the present study suggests that planarity of coralyne results in a more favorable and stronger binding to the double-stranded RNA conformations compared to berberine and palmatine that may potentiate its use in RNA-targeted drug design.

  • rna targeting by small molecule alkaloids studies on the binding of berberine and palmatine to Polyribonucleotides and comparison to ethidium
    Journal of Molecular Structure, 2008
    Co-Authors: Md Maidul Islam, Gopinatha Suresh Kumar
    Abstract:

    Abstract The binding affinity, energetics and conformational aspects of the interaction of isoquinoline alkaloids berberine and palmatine to four single stranded Polyribonucleotides polyguanylic acid [poly(G)], polyinosinic acid [poly(I)], polycytidylic acid [poly(C)] and polyuridylic acid [poly(U)] were studied by absorption, fluorescence, isothermal titration calorimetry and circular dichroism spectroscopy and compared with ethidium. Berberine, palmatine and ethidium binds strongly with poly(G) and poly(I) with affinity in the order 105 M−1 while their binding to poly(C) and poly(U) were very weak or practically nil. The same conclusions have also emerged from isothermal titration calorimetric studies. The binding of all the three compounds to poly(C) and poly(I) was exothermic and favored by both negative enthalpy change and positive entropy change. Conformational change in the polymer associated with the binding was observed in poly(I) with all the three molecules and poly(U) with ethidium but not in poly(G) and poly(C) revealing differences in the orientation of the bound molecules in the hitherto different helical organization of these polymers. These fundamental results may be useful and serve as database for the development of futuristic RNA based small molecule therapeutics.

Alexander S Spirin - One of the best experts on this subject based on the ideXlab platform.

  • internal initiation of polyuridylic acid translation in bacterial cell free system
    Biochemistry, 2013
    Co-Authors: E A Sogorin, Ch S Agalarov, Alexander S Spirin
    Abstract:

    The task of the present work was to answer the question: is the free 5'-end needed for effective translation of a model Polyribonucleotide template - polyuridylic acid - in a bacterial (E. coli) cell-free system? For this purpose, the template activities of the original polyuridylic acid with its free 5'-end and the polyuridylic acid with blocked 5'-end were compared in the bacterial cell-free translation system. To block the 5'-end, the cytidylic oligodeoxyribonucleotide with fluorescein residue at its 5'-end and uridylic oligoribonucleotide sequence at its 3'-end, schematically described as FAM(dC)10(rU)50, was covalently attached (ligated) to the 5'-end of the template polyuridylic acid. It was shown that the efficiency of polyphenylalanine synthesis on the 5'-blocked template and on the polyuridylic acid with free 5'-end was virtually the same. It was concluded that bacterial ribosomes are capable of effectively initiating translation at the polyuridylic sequence independently of the 5'-end of template Polyribonucleotide, i.e. via an internal initiation mechanism, in the absence of a Shine-Dalgarno sequence and AUG start codon.

  • the leader sequence of tobacco mosaic virus rna devoid of watson crick secondary structure possesses a cooperatively melted compact conformation
    Biochemical and Biophysical Research Communications, 2007
    Co-Authors: Alexey A Kovtun, Nikolay E Shirokikh, A T Gudkov, Alexander S Spirin
    Abstract:

    Abstract The 5′-untranslated region (5′-UTR) of RNA of tobacco mosaic virus (TMV), called omega sequence, is known as an mRNA leader promoting efficient initiation of translation. The central part of the sequence consists of many CAA repeats, which were reported to be mainly responsible for the enhancing activity of the omega leader. In this work we synthesized the Polyribonucleotides containing either the natural omega sequence or the regular (CAA) n sequence, and studied them using UV spectrophotometry and analytical ultracentrifugation methods. It was demonstrated that the Polyribonucleotides manifest significant hypochromicity, cooperative melting of their structures upon heating, high melting temperature, and the sedimentation coefficients typical of compactly folded RNAs of this size. Thus, the omega leader and its core (CAA) n repeat sequence devoid of secondary structure of the Watson–Crick type seem to be well structured elements of mRNA.

Ghosh S. - One of the best experts on this subject based on the ideXlab platform.

  • Prevention of dsRNA-induced interferon signaling by AGO1x is linked to breast cancer cell proliferation.
    'EMBO', 2020
    Co-Authors: Ghosh S., Guimaraes J. C), Lanzafame M., Schmidt A., Syed A. Pasha), Dimitriades B., Börsch A., Mittal N., Montavon T.
    Abstract:

    Translational readthrough, i.e., elongation of polypeptide chains beyond the stop codon, was initially reported for viral RNA, but later found also on eukaryotic transcripts, resulting in proteome diversification and protein-level modulation. Here, we report that AGO1x, an evolutionarily conserved translational readthrough isoform of Argonaute 1, is generated in highly proliferative breast cancer cells, where it curbs accumulation of double-stranded RNAs (dsRNAs) and consequent induction of interferon responses and apoptosis. In contrast to other mammalian Argonaute protein family members with primarily cytoplasmic functions, AGO1x exhibits nuclear localization in the vicinity of nucleoli. We identify AGO1x interaction with the Polyribonucleotide nucleotidyltransferase 1 (PNPT1) and show that the depletion of this protein further augments dsRNA accumulation. Our study thus uncovers a novel function of an Argonaute protein in buffering the endogenous dsRNA-induced interferon responses, different than the canonical function of AGO proteins in the miRNA effector pathway. As AGO1x expression is tightly linked to breast cancer cell proliferation, our study thus suggests a new direction for limiting tumor growth.journal article2020 Aug 192020 08 19importe

John P Mordes - One of the best experts on this subject based on the ideXlab platform.

  • polyinosinic polycytidylic acid is a potent activator of endothelial cells
    American Journal of Pathology, 1994
    Co-Authors: John Doukas, Anne H Cutler, John P Mordes
    Abstract:

    Polyinosinic:polycytidylic acid (poly I:C) is a synthetic double-stranded Polyribonucleotide that elicits immune responses analogous to those observed during viral infection. It is also known to modulate the expression of certain autoimmune disorders including diabetes mellitus in the BB rat and NOD mouse. The mechanism underlying these immunomodulatory effects is not known, but it could involve activation of vascular endothelium. We now report that parenteral poly I:C induces rat pancreatic endothelium to hyperexpress intercellular adhesion molecule 1 (CD54). This is accompanied by a perivascular recruitment of mononuclear cells to the exocrine pancreas. Corollary in vitro studies demonstrated that poly I:C is a potent activator of both rat and human endothelial cells in culture. It upregulates endothelial expression of several leukocyte adhesion molecules, stimulates the release of interleukin-6 and interleukin-8, and antagonizes interferon-gamma induction of major histocompatibility complex class II expression. We conclude that poly I:C activates endothelial cells to express surface molecules and cytokines in a pattern classically associated with leukocyte recruitment. These effects may in part contribute to the immunomodulatory effects of poly I:C in animal models of autoimmunity.

Montavon T. - One of the best experts on this subject based on the ideXlab platform.

  • Prevention of dsRNA-induced interferon signaling by AGO1x is linked to breast cancer cell proliferation.
    'EMBO', 2020
    Co-Authors: Ghosh S., Guimaraes J. C), Lanzafame M., Schmidt A., Syed A. Pasha), Dimitriades B., Börsch A., Mittal N., Montavon T.
    Abstract:

    Translational readthrough, i.e., elongation of polypeptide chains beyond the stop codon, was initially reported for viral RNA, but later found also on eukaryotic transcripts, resulting in proteome diversification and protein-level modulation. Here, we report that AGO1x, an evolutionarily conserved translational readthrough isoform of Argonaute 1, is generated in highly proliferative breast cancer cells, where it curbs accumulation of double-stranded RNAs (dsRNAs) and consequent induction of interferon responses and apoptosis. In contrast to other mammalian Argonaute protein family members with primarily cytoplasmic functions, AGO1x exhibits nuclear localization in the vicinity of nucleoli. We identify AGO1x interaction with the Polyribonucleotide nucleotidyltransferase 1 (PNPT1) and show that the depletion of this protein further augments dsRNA accumulation. Our study thus uncovers a novel function of an Argonaute protein in buffering the endogenous dsRNA-induced interferon responses, different than the canonical function of AGO proteins in the miRNA effector pathway. As AGO1x expression is tightly linked to breast cancer cell proliferation, our study thus suggests a new direction for limiting tumor growth.journal article2020 Aug 192020 08 19importe