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Ge, X., Oliveira, A., Hjort, K., Bergfors, T., Gutiérrez-de-Terán, H., Andersson, D. I., . . . Åqvist, J. (2019). Inhibition of translation termination by small molecules targeting ribosomal release factors. Scientific Reports, 9, Article ID 15424.
Open this publication in new window or tab >>Inhibition of translation termination by small molecules targeting ribosomal release factors
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 15424Article in journal (Refereed) Published
Abstract [en]

The bacterial ribosome is an important drug target for antibiotics that can inhibit different stages of protein synthesis. Among the various classes of compounds that impair translation there are, however, no known small-molecule inhibitors that specifically target ribosomal release factors (RFs). The class I RFs are essential for correct termination of translation and they differ considerably between bacteria and eukaryotes, making them potential targets for inhibiting bacterial protein synthesis. We carried out virtual screening of a large compound library against 3D structures of free and ribosome-bound RFs in order to search for small molecules that could potentially inhibit termination by binding to the RFs. Here, we report identification of two such compounds which are found both to bind free RFs in solution and to inhibit peptide release on the ribosome, without affecting peptide bond formation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medicinal Chemistry Structural Biology
Identifiers
urn:nbn:se:uu:diva-396310 (URN)10.1038/s41598-019-51977-1 (DOI)000492832300009 ()31659219 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish National Infrastructure for Computing (SNIC)
Available from: 2019-11-01 Created: 2019-11-01 Last updated: 2019-11-18Bibliographically approved
Cordeiro, Y., Vieira, T., Kovachev, P. S., Sanyal, S. & Silva, J. L. (2019). Modulation of p53 and prion protein aggregation by RNA. Biochimica et Biophysica Acta - Proteins and Proteomics, 1867(10), 933-940
Open this publication in new window or tab >>Modulation of p53 and prion protein aggregation by RNA
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2019 (English)In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1867, no 10, p. 933-940Article, review/survey (Refereed) Published
Abstract [en]

Several RNA-binding proteins undergo reversible liquid-liquid phase transitions, which, in pathological conditions, might evolve into transitions to solid-state phases, giving rise to amyloid structures. Amyloidogenic and prion-like proteins, such as the tumor suppressor protein p53 and the mammalian prion protein (PrP), bind RNAs specifically or nonspecifically, resulting in changes in their propensity to undergo aggregation. Mutant p53 aggregation seems to play a crucial role in cancer through loss of function, negative dominance and gain of function. PrP conversion modulated by RNA results in highly toxic aggregates. Here, we review data on the modulatory action of RNAs on the aggregation of both proteins.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-393757 (URN)10.1016/j.bbapap.2019.02.006 (DOI)000480375700008 ()30826454 (PubMedID)
Available from: 2019-09-27 Created: 2019-09-27 Last updated: 2019-09-27Bibliographically approved
Kovachev, P. S., Gomes, M. P. B., Cordeiro, Y., Ferreira, N. C., Felix Valadao, L. P., Ascari, L. M., . . . Sanyal, S. (2019). RNA modulates aggregation of the recombinant mammalian prion protein by direct interaction. Scientific Reports, 9, Article ID 12406.
Open this publication in new window or tab >>RNA modulates aggregation of the recombinant mammalian prion protein by direct interaction
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 12406Article in journal (Refereed) Published
Abstract [en]

Recent studies have proposed that nucleic acids act as potential cofactors for protein aggregation and prionogenesis. By means of sedimentation, transmission electron microscopy, circular dichroism, static and dynamic light scattering, we have studied how RNA can influence the aggregation of the murine recombinant prion protein (rPrP). We find that RNA, independent of its sequence, source and size, modulates rPrP aggregation in a bimodal fashion, affecting both the extent and the rate of rPrP aggregation in a concentration dependent manner. Analogous to RNA-induced liquid-liquid phase transitions observed for other proteins implicated in neurodegenerative diseases, high protein to RNA ratios stimulate rPrP aggregation, while low ratios suppress it. However, the latter scenario also promotes formation of soluble oligomeric aggregates capable of seeding de novo rPrP aggregation. Furthermore, RNA co-aggregates with rPrP and thereby gains partial protection from RNase digestion. Our results also indicate that rPrP interacts with the RNAs with its N-terminus. In summary, this study elucidates the proposed adjuvant role of RNA in prion protein aggregation and propagation, and thus advocates an auxiliary role of the nucleic acids in protein aggregation in general.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-398847 (URN)10.1038/s41598-019-48883-x (DOI)000482709400017 ()31455808 (PubMedID)
Funder
Swedish Research Council, 2016-06264Swedish Research Council, 2018-05498Knut and Alice Wallenberg Foundation, KAW 2017.0055Swedish Research Council, BR2013-5223The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), BR2013-5223The Wenner-Gren Foundation, UPD2017-0238The Wenner-Gren Foundation, UPD2018-0306
Note

Manuscript title: Direct involvement of RNA in mammalian prion protein aggregation: Involvement of RNA in rPrP aggregation

Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2019-12-19Bibliographically approved
Holm, M., Mandava, C. S., Ehrenberg, M. & Sanyal, S. (2019). The mechanism of error induction by the antibiotic viomycin provides insight into the fidelity mechanism of translation. eLIFE, 8, Article ID e46124.
Open this publication in new window or tab >>The mechanism of error induction by the antibiotic viomycin provides insight into the fidelity mechanism of translation
2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e46124Article in journal (Refereed) Published
Abstract [en]

Applying pre-steady state kinetics to an Escherichia-coli-based reconstituted translation system, we have studied how the antibiotic viomycin affects the accuracy of genetic code reading. We find that viomycin binds to translating ribosomes associated with a ternary complex (TC) consisting of elongation factor Tu (EF-Tu), aminoacyl tRNA and GTP, and locks the otherwise dynamically flipping monitoring bases A1492 and A1493 into their active conformation. This effectively prevents dissociation of near- and non-cognate TCs from the ribosome, thereby enhancing errors in initial selection. Moreover, viomycin shuts down proofreading-based error correction. Our results imply a mechanism in which the accuracy of initial selection is achieved by larger backward rate constants toward TC dissociation rather than by a smaller rate constant for GTP hydrolysis for near- and non-cognate TCs. Additionally, our results demonstrate that translocation inhibition, rather than error induction, is the major cause of cell growth inhibition by viomycin.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-390687 (URN)10.7554/eLife.46124 (DOI)000473013700001 ()31172942 (PubMedID)
Funder
Swedish Research Council, 2018-05498Swedish Research Council, 2016-06264Knut and Alice Wallenberg Foundation, KAW 2011.0081Knut and Alice Wallenberg Foundation, KAW 2017.0055Carl Tryggers foundation , CTS 18: 338Wenner-Gren Foundations, UPD2017-0238
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
Vovusha, H., Banerjee, D., Yadav, M. K., Perrozzi, F., Ottaviano, L., Sanyal, S. & Sanyal, B. (2018). Binding Characteristics of Anticancer Drug Doxorubicin with Two-Dimensional Graphene and Graphene Oxide: Insights from Density Functional Theory Calculations and Fluorescence Spectroscopy. The Journal of Physical Chemistry C, 122(36), 21031-21038
Open this publication in new window or tab >>Binding Characteristics of Anticancer Drug Doxorubicin with Two-Dimensional Graphene and Graphene Oxide: Insights from Density Functional Theory Calculations and Fluorescence Spectroscopy
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2018 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 122, no 36, p. 21031-21038Article in journal (Refereed) Published
Abstract [en]

There has been a perpetual interest in identifying suitable nano-carriers for drug delivery. In this regard, graphene-based two-dimensional materials have been proposed and demonstrated as drug carriers. In this paper, we have investigated the adsorption characteristics of a widely used anticancer drug, doxorubicin (DOX), on graphene (G) and graphene oxide (GO) by density functional theory calculations and fluorescence and X-ray photoelectron spectroscopies. From the calculated structural and electronic properties, we have concluded that G is a better binder of DOX compared to GO, which is also supported by our fluorescence measurements. The binding of DOX to G is mainly based on strong pi-pi stacking interactions. Consistent with this result, we also found that the sp(2) regions of GO interact with DOX stronger than the sp(3) regions attached with the functional groups; the binding is characterized by pi-pi and hydrogen-bonding interactions, respectively.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-366741 (URN)10.1021/acs.jpcc.8b04496 (DOI)000444920900049 ()
Funder
Swedish Research Council, 2016-05366Swedish Research Council, 20144423Swedish Research Council, 2017-05447Knut and Alice Wallenberg Foundation, KAW 2017.0055
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2019-05-17Bibliographically approved
Mishra, A. K., Morgon, N. H., Sanyal, S., de Souza, A. R. & Biswas, S. (2018). Catalytic O- to N-Alkyl Migratory Rearrangement: Transition Metal-Free Direct and Tandem Routes to N-Alkylated Pyridones and Benzothiazolones. Advanced Synthesis and Catalysis, 360(20), 3930-3939
Open this publication in new window or tab >>Catalytic O- to N-Alkyl Migratory Rearrangement: Transition Metal-Free Direct and Tandem Routes to N-Alkylated Pyridones and Benzothiazolones
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2018 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 360, no 20, p. 3930-3939Article in journal (Refereed) Published
Abstract [en]

The present study reports the synthesis of N-alkylated pyridones and benzothiazolones via O- to N-alkyl group migration under transition metal-free TfOH-catalyzed reaction conditions for the first time, to the best of our knowledge. Primary as well as secondary alkyl groups smoothly migrate under the present reaction conditions. Moreover, a minor modification of the protocol used in this study is found to be applicable for an entirely new tandem synthesis of 2-alkoxy-N-heterocycles from the simplest starting materials in a solvent-free reaction conditions. Density Functional Theory (DFT) calculation identifies the energy species associated with the rearrangement, whereas, mechanistic experiments explore the role of the catalyst as the alkyl group transfer mediator.

Place, publisher, year, edition, pages
WILEY-V C H VERLAG GMBH, 2018
Keywords
Benzothiazolones, Metal-free, Pyridones, Rearrangement, Tandem, DFT
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-369093 (URN)10.1002/adsc.201800664 (DOI)000447633800012 ()
Available from: 2019-02-18 Created: 2019-02-18 Last updated: 2019-02-18Bibliographically approved
Ge, X., Mandava, C. S., Lind, C., Åqvist, J. & Sanyal, S. (2018). Complementary charge-based interaction between the ribosomal-stalk protein L7/12 and IF2 is the key to rapid subunit association. Proceedings of the National Academy of Sciences of the United States of America, 115(18), 4649-4654
Open this publication in new window or tab >>Complementary charge-based interaction between the ribosomal-stalk protein L7/12 and IF2 is the key to rapid subunit association
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 18, p. 4649-4654Article in journal (Refereed) Published
Abstract [en]

The interaction between the ribosomal-stalk protein L7/12 (L12) and initiation factor 2 (IF2) is essential for rapid subunit association, but the underlying mechanism is unknown. Here, we have characterized the L12–IF2 interaction on Escherichia coli ribosomes using site-directed mutagenesis, fast kinetics, and molecular dynamics (MD) simulations. Fifteen individual point mutations were introduced into the C-terminal domain of L12 (L12-CTD) at helices 4 and 5, which constitute the common interaction site for translational GTPases. In parallel, 15 point mutations were also introduced into IF2 between the G4 and G5 motifs, which we hypothesized as the potential L12 interaction sites. The L12 and IF2 mutants were tested in ribosomal subunit association assay in a stopped-flow instrument. Those amino acids that caused defective subunit association upon substitution were identified as the molecular determinants of L12–IF2 interaction. Further, MD simulations of IF2 docked onto the L12-CTD pinpointed the exact interacting partners—all of which were positively charged on L12 and negatively charged on IF2, connected by salt bridges. Lastly, we tested two pairs of charge-reversed mutants of L12 and IF2, which significantly restored the yield and the rate of formation of the 70S initiation complex. We conclude that complementary charge-based interaction between L12-CTD and IF2 is the key for fast subunit association. Considering the homology of the G domain, similar mechanisms may apply for L12 interactions with other translational GTPases.

Keywords
protein synthesis, ribosomal protein L7/12, protein-protein interaction, ribosome, translation initiation
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-350185 (URN)10.1073/pnas.1802001115 (DOI)000431119600050 ()29686090 (PubMedID)
Funder
Swedish Research Council, 2014-4423; 2016-06264Knut and Alice Wallenberg Foundation, 2011.0081VINNOVA, 2013-8778
Available from: 2018-05-07 Created: 2018-05-07 Last updated: 2018-07-13Bibliographically approved
Fislage, M., Zhang, J., Brown, Z. P., Mandava, C. S., Sanyal, S., Ehrenberg, M. & Frank, J. (2018). Cryo-EM shows stages of initial codon selection on the ribosome by aa-tRNA in ternary complex with GTP and the GTPase-deficient EF-Tu(H84A). Nucleic Acids Research, 46(11), 5861-5874
Open this publication in new window or tab >>Cryo-EM shows stages of initial codon selection on the ribosome by aa-tRNA in ternary complex with GTP and the GTPase-deficient EF-Tu(H84A)
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2018 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 11, p. 5861-5874Article in journal (Refereed) Published
Abstract [en]

The GTPase EF-Tu in ternary complex with GTP and aminoacyl-tRNA (aa-tRNA) promotes rapid and accurate delivery of cognate aa-tRNAs to the ribosomal A site. Here we used cryo-EM to study the molecular origins of the accuracy of ribosome-aided recognition of a cognate ternary complex and the accuracy-amplifying role of themonitoring bases A1492, A1493 and G530 of the 16S rRNA. We used the GTPase-deficient EF-Tu variant H84A with native GTP, rather than non-cleavable GTP analogues, to trap a near-cognate ternary complex in high-resolution ribosomal complexes of varying codon-recognition accuracy. We found that ribosome complexes trapped by GTPase-deficicent ternary complex due to the presence of EF-TuH84A or non-cleavable GTP analogues have very similar structures. We further discuss speed and accuracy of initial aa-tRNA selection in terms of conformational changes of aa-tRNA and stepwise activation of the monitoring bases at the decoding center of the ribosome.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-361119 (URN)10.1093/nar/gky346 (DOI)000438362400042 ()29733411 (PubMedID)
Funder
Swedish Research Council, 2013-8778Swedish Research Council, 2014-4423Swedish Research Council, 2016-06264Swedish Research Council, 2017-00230Knut and Alice Wallenberg Foundation, KAW 2011.0081NIH (National Institute of Health), R01 GM29169
Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-09-20Bibliographically approved
Li, Z., Ge, X., Zhang, Y., Zheng, L., Sanyal, S. & Gao, N. (2018). Cryo-EM structure of Mycobacterium smegmatis ribosome reveals two unidentified ribosomal proteins close to the functional centers [Letter to the editor]. Protein & cell, 9(4), 384-388
Open this publication in new window or tab >>Cryo-EM structure of Mycobacterium smegmatis ribosome reveals two unidentified ribosomal proteins close to the functional centers
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2018 (English)In: Protein & cell, ISSN 1674-8018, Vol. 9, no 4, p. 384-388Article in journal, Letter (Other academic) Published
National Category
Microbiology Cell Biology
Identifiers
urn:nbn:se:uu:diva-344575 (URN)10.1007/s13238-017-0456-9 (DOI)000428849800007 ()28875450 (PubMedID)
Funder
Swedish Research Council, 2013-8778; 2014-4423; 2016-06264; 2008-6593Knut and Alice Wallenberg Foundation, KAW 2011.0081
Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-08-10Bibliographically approved
Vieler, M. & Sanyal, S. (2018). p53 Isoforms and Their Implications in Cancer. Cancers, 10(9), Article ID 288.
Open this publication in new window or tab >>p53 Isoforms and Their Implications in Cancer
2018 (English)In: Cancers, ISSN 2072-6694, Vol. 10, no 9, article id 288Article, review/survey (Refereed) Published
Abstract [en]

In this review we focus on the major isoforms of the tumor-suppressor protein p53, dysfunction of which often leads to cancer. Mutations of the TP53 gene, particularly in the DNA binding domain, have been regarded as the main cause for p53 inactivation. However, recent reports demonstrating abundance of p53 isoforms, especially the N-terminally truncated ones, in the cancerous tissues suggest their involvement in carcinogenesis. These isoforms are Delta 40p53, Delta 133p53, and Delta 160p53 (the names indicate their respective N-terminal truncation). Due to the lack of structural and functional characterizations the modes of action of the p53 isoforms are still unclear. Owing to the deletions in the functional domains, these isoforms can either be defective in DNA binding or more susceptive to altered 'responsive elements' than p53. Furthermore, they may exert a 'dominant negative effect' or induce more aggressive cancer by the 'gain of function'. One possible mechanism of p53 inactivation can be through tetramerization with the Delta 133p53 and Delta 160p53 isoforms-both lacking part of the DNA binding domain. A recent report and unpublished data from our laboratory also suggest that these isoforms may inactivate p53 by fast aggregation-possibly due to ectopic overexpression. We further discuss the evolutionary significance of the p53 isoforms.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
p53, cancer, p53 isoform, Delta 133p53, Delta 160p53, Delta 40p53, aggregation, prion
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-370049 (URN)10.3390/cancers10090288 (DOI)000448139800012 ()30149602 (PubMedID)
Funder
Swedish Research Council, 2014-4423Swedish Research Council, 2016-06264Knut and Alice Wallenberg Foundation, KAW 2017.0055
Available from: 2018-12-20 Created: 2018-12-20 Last updated: 2018-12-20Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-7124-792X

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