Article
Biochemistry & Molecular Biology
Heidi Zetzsche, Laura Raschke, Boris Fuertig
Summary: In this study, the activation mechanism of RhlB by RNase E was investigated using NMR spectroscopy and an RNA centered approach. The results showed that RNase E binding increases the affinity of RhlB towards certain RNA substrates, leading to increased ATP turnover rates. The study also revealed a unique activation mode of RhlB among DEAD-Box helicases, as it can induce partial duplex opening of RNA even in the absence of ATP.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Biology
Calvin M. Schmidt, Christina D. Smolke
Summary: Ribozyme switches are RNA-encoded genetic switches that enable conditional regulation of gene expression; researchers developed predictive models using large data sets and machine learning to design new ribozyme switches with gene-regulatory activity.
Article
Biochemistry & Molecular Biology
Katherine E. Berman, Russell Steans, Laura M. Hertz, Julius B. Lucks
Summary: This study investigates the involvement of intermediate structures in translation controlling riboswitches, specifically focusing on the thiB riboswitch. The results demonstrate the presence of an intermediate structure called the antisequestering stem, which competes with the AD and EP folds to implement the riboswitch mechanism.
Review
Chemistry, Physical
Claire Husser, Natacha Dentz, Michael Ryckelynck
Summary: RNA plays a crucial role in cell life, particularly in gene expression regulation. Riboswitches, as cis-acting molecules, are able to specifically sense a target ligand and control the expression of downstream genes without the need for cellular factors, making them highly portable and potentially useful in various applications such as gene therapy and biosensing of small molecules.
Article
Chemistry, Multidisciplinary
Diana Muller, Irene Bessi, Christian Richter, Harald Schwalbe
Summary: The folding kinetics of RNA G4 and DNA G4 differ significantly during K+-induced folding, mainly due to differences in their folded conformations, especially regarding the chi angle preferences. Modified DNA G4 can achieve faster folding kinetics and monomorphic conformations similar to RNA G4 by adjusting the chi angle.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Genetics & Heredity
Gongwang Yu, Hanbing Zhu, Xiaoshu Chen, Jian-Rong Yang
Summary: The study investigates the secondary structure characteristics of mRNAs and their importance in function and evolution. It is found that specific folding of mRNAs may be an adaptive trait associated with important genes or sites, potentially providing the advantage of modulating ribosome movement. This reveals a novel aspect of the RNA structurome with functional and evolutionary implications.
GENOMICS PROTEOMICS & BIOINFORMATICS
(2021)
Review
Biochemistry & Molecular Biology
Agnieszka Chelkowska-Pauszek, Jan Grzegorz Kosinski, Klementyna Marciniak, Marta Wysocka, Kamilla Bakowska-Zywicka, Marek Zywicki
Summary: Bacteria have developed mechanisms for immediate adjustment of gene expression in response to changing environmental conditions, often relying on RNA-dependent regulatory mechanisms. The high dynamics and flexibility of RNA structure provide the necessary sensitivity and specificity for efficient sensing and transduction of environmental signals. This review discusses bacterial regulatory mechanisms based on RNA structure and presents examples of RNA regulators' multiple mechanisms in controlling bacterial transcription and translation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Rika Ichijo, Takashi Kamimura, Gota Kawai
Summary: RNA-targeted small molecules show promise in drug discovery. A fluoroquinolone derivative, KG022, has been found to bind to RNAs with bulged C or G. The specificity of KG022 for RNA was analyzed and it was shown to prefer G-C and A-U base pairs at the 3' side of the bulged residue. The solution structures of KG022 complexes with four RNA molecules were determined, revealing that the fluoroquinolone moiety is located between two purine bases, providing insights into the specificity mechanism. This work highlights the importance of RNA-targeted small molecules and their specificity.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2023)
Article
Endocrinology & Metabolism
Yanwu Yang, Michael D. Glidden, Balamurugan Dhayalan, Alexander N. Zaykov, Yen-Shan Chen, Nalinda P. Wickramasinghe, Richard D. DiMarchi, Michael A. Weiss
Summary: This article investigates the toxic misfolding of diabetes-associated proteins in beta-cells, and proposes a peptide model for classifying related mutations. The study found that the mutant variants exhibit successive structural perturbations, which are correlated with the phenotypic differences in diabetes.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Zhihua Chang, Ya Ying Zheng, Johnsi Mathivanan, Vibhav A. Valsangkar, Jinxi Du, Reham A. Abou-Elkhair, Abdalla E. A. Hassan, Jia Sheng
Summary: This study investigated whether sisomicin, previously known to bind HIV-1 TAR, can act as a ligand for CUG RNA repeats. It was found that sisomicin can bind and stabilize the folded RNA structure through the change of fluorescent signal. Additionally, a fluorescence-based binding characterization assay was developed and proved to be consistent with the classic UV T-m technique, demonstrating its feasibility for high-throughput screening of ligand-RNA binding interactions and measurement of thermodynamic parameters.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biology
Luqian Zheng, Qianqian Song, Xiaochen Xu, Xin Shen, Chunyan Li, Hongcheng Li, Hao Chen, Aiming Ren
Summary: Riboswitches are conserved RNA elements that regulate downstream gene expression by undergoing conformational changes upon ligand binding. The SAM riboswitch is one of the most abundant riboswitches, specifically binding to SAM and serving as a regulatory module in metabolic pathways. Several SAM-specific riboswitch families with well-organized core scaffolds have been identified, and their distribution, structure, ligand recognition, gene regulation mechanism, evolutionary prospects, and potential applications are summarized in this review.
SCIENCE CHINA-LIFE SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Jan H. Overbeck, Jennifer Vogele, Felix Nussbaumer, Elke Duchardt-Ferner, Christoph Kreutz, Jens Wohnert, Remco Sprangers
Summary: The synthetic neomycin-sensing riboswitch interacts with neomycin, ribostamycin, and paromomycin. However, only neomycin can efficiently repress translation initiation due to differences in ligand:riboswitch dynamics. Five complementary fluorine-based NMR methods were used to accurately quantify dynamics in the riboswitch complexes and identified four structurally different states. These findings highlight the potential of F-19 NMR methods in characterizing complex exchange processes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Multidisciplinary Sciences
Sicong Ma, Anita Kotar, Ian Hall, Scott Grote, Silvi Rouskin, Sarah C. Keane
Summary: As an essential regulator of gene expression, microRNA levels must be maintained strictly. The structural properties of the precursor element of miR-31 play a role in regulating its biogenesis. The size of the apical loop and the structure at the Dicing site are key elements for discrimination by the Dicer-TRBP complex.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Tom Dendooven, Elisabeth Sonnleitner, Udo Blaesi, Ben F. Luisi
Summary: The bacterial RNA chaperone Hfq and its partner protein Crc form higher order assemblies on control regions of different P. aeruginosa target mRNAs. These assemblies have mRNA-specific quaternary architectures due to the combination of multivalent protein-protein interfaces and recognition of patterns in the RNA sequence. The structural polymorphism of these ribonucleoprotein assemblies enables selective translational repression of many different target mRNAs.
Review
Pharmacology & Pharmacy
Andrea Criscuolo, Ettore Napolitano, Claudia Riccardi, Domenica Musumeci, Chiara Platella, Daniela Montesarchio
Summary: G-quadruplexes are important targets for anticancer/antiviral therapies. Over 3000 small-molecule ligands have been described, which exert their activity by damaging telomeres or altering gene expression in cancer cells and viruses. Detailed knowledge on the interactions between ligands and G-quadruplexes has been obtained through NMR and crystallographic studies.
Article
Cardiac & Cardiovascular Systems
S. Engelhardt, S. Dimmeler, C. Heim, C. Baer, T. Boettger, R. Boon, R. P. Brandes, T. Braun, A. Dueck, J. Gagneur, P. Grote, L. M. Holdt, N. Jae, J. Krishnan, C. Kupatt, K. -l. Laugwitz, M. S. Leisegang, L. Maegdefessel, T. Meitinger, A. Moretti, M. Mueller-McNicoll, M. Sattler, A. Schnieke, M. Schulz, H. Schunkert, H. Schwalbe, D. Teupser, T. Thum, C. Weber, I. Wittig, K. Zarnack
Summary: The discovery of regulatory noncoding RNA molecules has revolutionized our understanding of gene expression. These RNA molecules, especially microRNAs, long noncoding RNAs, and circular RNAs, play important roles in the cardiovascular system and have potential for therapeutic applications. However, the complexity of RNA transcripts and the mechanisms of their actions present significant challenges for further research.
Article
Biochemistry & Molecular Biology
Jennifer Bremer, Christian Richter, Harald Schwalbe, Clemens Richert
Summary: Peptidoyl RNAs are translation products of single-nucleotide without the involvement of ribosomes, containing peptide structures in their oligoribonucleotide backbones. A research team has developed a method to synthesize a stable version of peptidoyl RNA with peptide linkages within the RNA chain. UV-melting and NMR analysis showed that the folding of the peptide-linked RNA segments is not cooperative. The synthesis of double RNA-linked peptides provides a new approach for exploring their structural and biochemical properties.
Article
Biochemistry & Molecular Biology
Aikaterini C. Tsika, Angelo Gallo, Nikolaos K. Fourkiotis, Aikaterini I. Argyriou, Sridhar Sreeramulu, Frank Loehr, Vladimir V. Rogov, Christian Richter, Verena Linhard, Santosh L. Gande, Nadide Altincekic, Robin Krishnathas, Isam Elamri, Harald Schwalbe, Jan Wollenhaupt, Manfred S. Weiss, Georgios A. Spyroulias
Summary: Viral infection triggers molecular defense mechanisms, including ADP-ribosylation. Viral macro domains, which can reverse ADP-ribosylation, are potential pharmaceutical targets. GS-441524, a metabolite of remdesivir, selectively inhibits viral macro domains.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Tom Landgraf, Albrecht Eduard Voelklein, Boris Fuertig, Harald Schwalbe
Summary: Riboswitches are gene regulatory elements located in untranslated mRNA regions that bind inducer molecules with high affinity and specificity. Understanding the interaction between cyclic-di-nucleotides and riboswitches provides insights into gene regulation mechanisms. Experimental and computational studies allow us to predict riboswitch gene regulation and its dependence on transcription speed, pausing, and ligand concentration.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Jan Heering, Nathalie Jores, Whitney Kilu, Espen Schallmayer, Evelyn Peelen, Andreas Muehler, Hella Kohlhof, Daniel Vitt, Verena Linhard, Santosh L. Gande, Apirat Chaikuad, Sridhar Sreeramulu, Harald Schwalbe, Daniel Merk
Summary: This study elucidates the molecular basis of FXR activation by systematically studying the response of FXR ligands. Different ligands have different effects on FXR activation, which align with structural changes in the ligand binding domain of FXR. The results suggest the potential application of selective modulation of FXR dimerization and co-regulator interactions for FXR ligands.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Marie-Theres Hutchison, Giovanni Bellomo, Alexey Cherepanov, Elke Stirnal, Boris Fuertig, Christian Richter, Verena Linhard, Elina Gurewitsch, Moreno Lelli, Nina Morgner, Thomas Schrader, Harald Schwalbe
Summary: This study investigates the aggregation process of A beta 42 protein, which is directly related to the pathogenesis of Alzheimer's disease. Real-time solution NMR spectroscopy is used to track the A beta 42 aggregation kinetics and analyze the impact of low-molecular-weight inhibitors. The findings reveal the differential effects of low-molecular-weight inhibitors on early-stage aggregation.
Article
Chemistry, Multidisciplinary
Alexey Sudakov, Bozana Knezic, Martin Hengesbach, Boris Fuertig, Elke Stirnal, Harald Schwalbe
Summary: More than 170 post-transcriptional modifications of RNAs have been identified. However, the detailed investigation of these modifications is limited due to the difficulty in producing large RNAs containing these modifications. This study reports the chemo-enzymatic synthesis of RNA modifications and fluorine-modified analogs, allowing the synthesis of large RNAs. The incorporation of labeled nucleotides in the riboswitch demonstrated the applicability of the modified large RNAs in characterizing RNA fold and dynamics.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Biochemistry & Molecular Biology
Stefan Kunert, Verena Linhard, Sara Weirich, Michel Choudalakis, Florian Osswald, Lisa Kraemer, Anja R. Koehler, Alexander Broehm, Jan Wollenhaupt, Harald Schwalbe, Albert Jeltsch
Summary: The highly expressed DNMT3A DNA methyltransferase and MECP2 methylation reader in neurons interact through their DNMT3A-ADD and MECP2-TRD domains, and the interaction between MECP2 regulates the activity and subnuclear localization of DNMT3A. The interface of these two domains was mapped, revealing that the ADD domain interacts with the TRD domain through the D529-D531 region, while the TRD domain interacts with the ADD domain through residues 214-228, including K219 and K223. The mutations at the ADD-TRD interface disrupt the cellular interaction of these proteins in NIH3T3 cells.
Editorial Material
Chemistry, Multidisciplinary
Elke Duchardt-Ferner, Jan Ferner, Boris Fuertig, Martin Hengesbach, Christian Richter, Andreas Schlundt, Sridhar Sreeramulu, Anna Wacker, Julia E. Weigand, Julia Wirmer-Bartoschek, Harald Schwalbe
Summary: The COVID-19 outbreak in December 2019 led to the establishment of international collaborations to understand and combat the virus. The NMR community has come together to study the genome and proteome of SARS-CoV-2 and test their interaction with low-molecular-weight binders. Due to the global pandemic and extended lockdowns, research has shifted from local collaborations to digital formats, allowing immediate discussion of unpublished results, data analysis, sample sharing, and coordinated research between more than 50 groups from 18 countries. Key lessons and challenges for post-pandemic research are discussed.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
J. Tassilo Grun, Jihyun Kim, Sundaresan Jayanthi, Adonis Lupulescu, Eriks Kupce, Harald Schwalbe, Lucio Frydman
Summary: Magnetization transfer experiments can provide site-specific information in nuclear magnetic resonance (NMR). Repeated saturation magnetization transfer (SMT) experiments can enhance connectivities revealed via the nuclear Overhauser effect (NOE), but may also lead to artifacts such as spill-over effects and NOE oversaturation. Another potential artifact arises when labile protons of interest are bound to 15N-labeled heteronuclei. These phenomena are experimentally demonstrated in this article, along with proposed solutions to overcome them.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Tamer Ali, Sandra Rogala, Nina M. Krause, Jasleen Kaur Bains, Maria-Theodora Melissari, Sandra Waehrisch, Harald Schwalbe, Bernhard G. Herrmann, Phillip Grote
Summary: Long non-coding RNAs can regulate cell function and other genes on the transcriptional level through mechanisms such as direct interaction with DNA and formation of RNA:dsDNA triplexes. In this study, we genetically deleted the triplex forming sequence from the lncRNA Fendrr in mice and found its partial requirement for Fendrr function in vivo. Loss of the triplex forming site in developing lungs led to dysregulation of gene programs associated with lung fibrosis, with some genes containing a triplex site directly at their promoter. We confirmed the formation of an RNA:dsDNA triplex with target promoters in vitro and implicated the synergistic role of Fendrr and the Wnt signaling pathway in lung fibrosis.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Analytical
Robert Tannenberg, Martin Paul, Bettina Roeder, Santosh L. Gande, Sridhar Sreeramulu, Krishna Saxena, Christian Richter, Harald Schwalbe, Claudia Swart, Michael G. Weller
Summary: Cardiac vascular diseases, especially acute myocardial infarction (AMI), are a major cause of death worldwide. In this study, a chemiluminescence-based immunosensor was developed for the rapid and accurate measurement of cardiac troponin I (cTnI), a specific biomarker for AMI diagnosis. The sensor achieved selective and quasi-online cTnI determination within ten minutes using a flow cell and a sensitive CMOS camera for optical readout. The sensitivity and selectivity of the sensor were tested with recombinant proteins and diluted blood plasma and serum, demonstrating its potential for clinical applications.
Article
Chemistry, Multidisciplinary
Alexey V. Cherepanov, Harald Schwalbe
Summary: The quest for atomic structures of microsecond reaction intermediates is a cutting-edge research in the field of biochemistry. However, there is currently a lack of experimental methods for preparing time-resolved samples. In this study, a single-turnover technique for nanosecond initiation and suspension of biomolecular reactions in the microsecond time domain is developed. The reactions can be started by temperature jump or direct mixing and stopped by hyperquenching in liquid cryogen at 77K. The diverse morphology of nanoscale glassy bodies, including thin sheets suitable for structure analysis by transmission electron cryomicroscopy, is observed. Furthermore, a novel method of concentrating reaction intermediates for structural studies using low-temperature techniques is presented.
Meeting Abstract
Medical Laboratory Technology
C. Swart, M. Weller, V. Delatour, M. Quaglia, M. Oztug, A. Gallo, H. Schwalbe, C. Cobbaert, A. Reid, A. Kessler, G. Nordin
CLINICA CHIMICA ACTA
(2022)
Meeting Abstract
Biophysics
Albrecht E. Voelklein, Tom Landgraf, Oliver Binas, Boris Fuertig, Christian Richter, Harald Schwalbe
BIOPHYSICAL JOURNAL
(2022)
