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  1. Article ; Online: NMR and circular dichroism data for domain 2 of the HCV NS5A protein phosphorylated by the Casein Kinase II

    Luiza M. Bessa / Robert Schneider / Xavier Hanoulle

    Data in Brief, Vol 17, Iss , Pp 325-

    2018  Volume 333

    Abstract: The Hepatitis C Virus (HCV)11 HCV: Hepatitis C Virus; HSQC: heteronuclear single-quantum coherence; NS5A: nonstructural protein 5A; NS5A-D2: domain 2 of the nonstructural protein 5A; CKII: Casein kinase II, NS5A-D2_CKII: NS5A-D2 phosphorylated by CKII; ... ...

    Abstract The Hepatitis C Virus (HCV)11 HCV: Hepatitis C Virus; HSQC: heteronuclear single-quantum coherence; NS5A: nonstructural protein 5A; NS5A-D2: domain 2 of the nonstructural protein 5A; CKII: Casein kinase II, NS5A-D2_CKII: NS5A-D2 phosphorylated by CKII; CSP: combined chemical shift perturbations; THP: (Tris(hydroxypropyl)phosphine). nonstructural 5A protein (NS5A) is a phosphoprotein (Evans et al., 2004; Ross-Thriepland and Harris, 2014) [1,2] composed of an N-terminal well-structured domain and two C-terminal intrinsically disordered domains (Moradpour et al., 2007; Bartenschlager et al., 2013; Badillo et al., 2017) [3–5]. So far, no precise molecular function has been identified for this viral protein (Ross-Thriepland and Harris, 2015) [6] which is required for viral replication (Tellinghuisen et al., 2008) [7]. In this article, we present datasets of NMR and circular dichroism analyses of the domain 2 of the HCV NS5A protein (NS5A-D2) phosphorylated in vitro by the Casein Kinase II (CKII) (Dal Pero et al., 2007; Clemens et al., 2015; Masak et al., 2014; Kim et al., 2014) [8–11]. We describe the in vitro phosphorylation of the serine 288 (pS288) of NS5A-D2 by CKII and report the circular dichroism spectrum of the phosphorylated domain (NS5-D2_CKII). This data article also contains the 1H, 15N and 13C NMR chemical shift assignments (HN, N, Cα, Cβ and C’) for the phosphorylated NS5A-D2 domain, and an assigned 1H,15N-HSQC spectrum is shown. The NMR data have been acquired on an 800 MHz spectrometer. These NMR data have been used to calculate both the 1H,15N combined chemical shift perturbations (CSP) induced by the phosphorylation of pS288 and the secondary structural propensity (SSP) scores that describe the structural tendencies in this intrinsically disordered domain. The circular dichroism spectrum and the SSP scores of NS5A-D2_CKII have been compared with those of unphosphorylated NS5A-D2 [12,13]. Keywords: HCV NS5A, NMR, Phosphorylation, IDP
    Keywords Computer applications to medicine. Medical informatics ; R858-859.7 ; Science (General) ; Q1-390
    Subject code 572
    Language English
    Publishing date 2018-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Exploring the Antitubercular Activity of Anthranilic Acid Derivatives

    Léo Faïon / Kamel Djaout / Catalin Pintiala / Catherine Piveteau / Florence Leroux / Alexandre Biela / Stéphanie Slupek / Rudy Antoine / Monika Záhorszká / Francois-Xavier Cantrelle / Xavier Hanoulle / Jana Korduláková / Benoit Deprez / Nicolas Willand / Alain R. Baulard / Marion Flipo

    Pharmaceuticals, Vol 16, Iss 335, p

    From MabA (FabG1) Inhibition to Intrabacterial Acidification

    2023  Volume 335

    Abstract: Mycobacterium tuberculosis , the pathogen that causes tuberculosis, is responsible for the death of 1.5 million people each year and the number of bacteria resistant to the standard regimen is constantly increasing. This highlights the need to discover ... ...

    Abstract Mycobacterium tuberculosis , the pathogen that causes tuberculosis, is responsible for the death of 1.5 million people each year and the number of bacteria resistant to the standard regimen is constantly increasing. This highlights the need to discover molecules that act on new M. tuberculosis targets. Mycolic acids, which are very long-chain fatty acids essential for M. tuberculosis viability, are synthesized by two types of fatty acid synthase (FAS) systems. MabA (FabG1) is an essential enzyme belonging to the FAS-II cycle. We have recently reported the discovery of anthranilic acids as MabA inhibitors. Here, the structure–activity relationships around the anthranilic acid core, the binding of a fluorinated analog to MabA by NMR experiments, the physico-chemical properties and the antimycobacterial activity of these inhibitors were explored. Further investigation of the mechanism of action in bacterio showed that these compounds affect other targets than MabA in mycobacterial cells and that their antituberculous activity is due to the carboxylic acid moiety which induces intrabacterial acidification.
    Keywords MabA inhibitors ; anthranilic acid ; FabG1 ; tuberculosis ; mycolic acids ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Subject code 540
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Domain 2 of Hepatitis C Virus Protein NS5A Activates Glucokinase and Induces Lipogenesis in Hepatocytes

    Laure Perrin-Cocon / Cindy Kundlacz / Clémence Jacquemin / Xavier Hanoulle / Anne Aublin-Gex / Marianne Figl / Jeremy Manteca / Patrice André / Pierre-Olivier Vidalain / Vincent Lotteau / Olivier Diaz

    International Journal of Molecular Sciences, Vol 23, Iss 919, p

    2022  Volume 919

    Abstract: Hepatitis C virus (HCV) relies on cellular lipid metabolism for its replication, and actively modulates lipogenesis and lipid trafficking in infected hepatocytes. This translates into an intracellular accumulation of triglycerides leading to liver ... ...

    Abstract Hepatitis C virus (HCV) relies on cellular lipid metabolism for its replication, and actively modulates lipogenesis and lipid trafficking in infected hepatocytes. This translates into an intracellular accumulation of triglycerides leading to liver steatosis, cirrhosis and hepatocellular carcinoma, which are hallmarks of HCV pathogenesis. While the interaction of HCV with hepatocyte metabolic pathways is patent, how viral proteins are able to redirect central carbon metabolism towards lipogenesis is unclear. Here, we report that the HCV protein NS5A activates the glucokinase (GCK) isoenzyme of hexokinases through its D2 domain (NS5A-D2). GCK is the first rate-limiting enzyme of glycolysis in normal hepatocytes whose expression is replaced by the hexokinase 2 (HK2) isoenzyme in hepatocellular carcinoma cell lines. We took advantage of a unique cellular model specifically engineered to re-express GCK instead of HK2 in the Huh7 cell line to evaluate the consequences of NS5A-D2 expression on central carbon and lipid metabolism. NS5A-D2 increased glucose consumption but decreased glycogen storage. This was accompanied by an altered mitochondrial respiration, an accumulation of intracellular triglycerides and an increased production of very-low density lipoproteins. Altogether, our results show that NS5A-D2 can reprogram central carbon metabolism towards a more energetic and glycolytic phenotype compatible with HCV needs for replication.
    Keywords hepatitis C virus ; NS5A ; glycolysis ; glucokinase ; lipogenesis ; human lipoprotein ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 570
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Binding mechanisms of intrinsically disordered proteins

    Luca Mollica / Luiza Mamigonian Bessa / Xavier Hanoulle / Malene Ringkjøbing Jensen / Martin Blackledge / Robert Schneider

    Frontiers in Molecular Biosciences, Vol

    theory, simulation, and experiment

    2016  Volume 3

    Abstract: In recent years, protein science has been revolutionized by the discovery of intrinsically disordered proteins (IDPs). In contrast to the classical paradigm that a given protein sequence corresponds to a defined structure and an associated function, we ... ...

    Abstract In recent years, protein science has been revolutionized by the discovery of intrinsically disordered proteins (IDPs). In contrast to the classical paradigm that a given protein sequence corresponds to a defined structure and an associated function, we now know that proteins can be functional in the absence of a stable three-dimensional structure. In many cases, disordered proteins or protein regions become structured, at least locally, upon interacting with their physiological partners. Many, sometimes conflicting, hypotheses have been put forward regarding the interaction mechanisms of IDPs and the potential advantages of disorder for protein-protein interactions. Whether disorder may increase, as proposed e.g. in the fly-casting hypothesis, or decrease binding rates, increase or decrease binding specificity, or what role pre-formed structure might play in interactions involving IDPs (conformational selection vs. induced fit), are subjects of intense debate. Experimentally, these questions remain difficult to address. Here, we review experimental studies of binding mechanisms of IDPs using NMR spectroscopy and transient kinetic techniques, as well as the underlying theoretical concepts and numerical methods that can be applied to describe these interactions at the atomic level. The available literature suggests that the kinetic and thermodynamic parameters characterizing interactions involving IDPs can vary widely and that there may be no single common mechanism that can explain the different binding modes observed experimentally. Rather, disordered proteins appear to make combined use of features such as pre-formed structure and flexibility, depending on the individual system and the functional context.
    Keywords Kinetics ; protein-protein interactions ; nuclear magnetic resonance (NMR) ; intrinsically disordered proteins ; molecular dynamics simulations ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2016-09-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Solution structure of the N-terminal domain of Mediator subunit MED26 and molecular characterization of its interaction with EAF1 and TAF7

    Lens, Zoé / Alexis Verger / Didier Monté / Elisabeth Ferreira / Frédérique Dewitte / François-Xavier Cantrelle / Isabelle Landrieu / Jean-Luc Baert / Marc Aumercier / Riccardo Peruzzini / Vincent Villeret / Xavier Hanoulle

    Journal of Molecular Biology. 2017,

    2017  

    Abstract: MED26 is a subunit of Mediator, a large complex central to the regulation of gene transcription by RNA Polymerase II (RNA Pol II). MED26 plays a role in the switch between the initiation and elongation phases of RNA Pol II-mediated transcription process. ...

    Abstract MED26 is a subunit of Mediator, a large complex central to the regulation of gene transcription by RNA Polymerase II (RNA Pol II). MED26 plays a role in the switch between the initiation and elongation phases of RNA Pol II-mediated transcription process. Regulation of these steps requires successive binding of MED26 N-Terminal domain (NTD) to TBP-associated factor 7 (TAF7) and EAF1 (Eleven-nineteen lysine-rich in leukemia-Associated Factor 1). In order to investigate the mechanism of regulation by MED26, MED26-NTD structure was solved by nuclear magnetic resonance spectroscopy (NMR), revealing a 4-helix bundle. EAF1 (239–268) and TAF7 (205–235) peptide interactions were both mapped to the same groove formed by H3 and H4 helices of MED26-NTD. Both interactions are characterized by dissociation constants in the 10-μM range. Further experiments revealed a folding-upon-binding mechanism that leads to the formation of EAF1 (N247-S260) and TAF7 (L214-S227) helices. Chemical shift perturbations and NOE contacts support the involvement of residues I222/F223 in anchoring TAF7 helix to a hydrophobic pocket of MED26-NTD, including residues L48, W80 and I84. In addition, Ala mutations of charged residues located in the C-terminal disordered part of TAF7 and EAF1 peptides affected the binding, with a loss of affinity characterized by a 10-time increase of dissociation constants. A structural model of MED26-NTD/TAF7 complex shows bi-partite components, combining ordered and disordered segments, as well as hydrophobic and electrostatic contributions to the binding. This study provides molecular detail that will help to decipher the mechanistic basis for the initiation to elongation switch-function mediated by MED26-NTD.
    Keywords dissociation ; DNA-directed RNA polymerase ; hydrophobicity ; models ; mutation ; nuclear magnetic resonance spectroscopy ; peptides ; RNA ; transcription (genetics)
    Language English
    Size p. .
    Publishing place Elsevier Ltd
    Document type Article
    Note Pre-press version
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2017.09.001
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: DEB025 (Alisporivir) inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerisation in domain II of NS5A.

    Lotte Coelmont / Xavier Hanoulle / Udayan Chatterji / Carola Berger / Joke Snoeck / Michael Bobardt / Precious Lim / Inge Vliegen / Jan Paeshuyse / Grégoire Vuagniaux / Anne-Mieke Vandamme / Ralf Bartenschlager / Philippe Gallay / Guy Lippens / Johan Neyts

    PLoS ONE, Vol 5, Iss 10, p e

    2010  Volume 13687

    Abstract: DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. It is currently being evaluated in phase II clinical trials. DEB025 binds to CypA, a peptidyl-prolyl cis- ... ...

    Abstract DEB025/Debio 025 (Alisporivir) is a cyclophilin (Cyp)-binding molecule with potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. It is currently being evaluated in phase II clinical trials. DEB025 binds to CypA, a peptidyl-prolyl cis-trans isomerase which is a crucial cofactor for HCV replication. Here we report that it was very difficult to select resistant replicons (genotype 1b) to DEB025, requiring an average of 20 weeks (four independent experiments), compared to the typically <2 weeks with protease or polymerase inhibitors. This indicates a high genetic barrier to resistance for DEB025. Mutation D320E in NS5A was the only mutation consistently selected in the replicon genome. This mutation alone conferred a low-level (3.9-fold) resistance. Replacing the NS5A gene (but not the NS5B gene) from the wild type (WT) genome with the corresponding sequence from the DEB025(res) replicon resulted in transfer of resistance. Cross-resistance with cyclosporine A (CsA) was observed, whereas NS3 protease and NS5B polymerase inhibitors retained WT-activity against DEB025(res) replicons. Unlike WT, DEB025(res) replicon replicated efficiently in CypA knock down cells. However, DEB025 disrupted the interaction between CypA and NS5A regardless of whether the NS5A protein was derived from WT or DEB025(res) replicon. NMR titration experiments with peptides derived from the WT or the DEB025(res) domain II of NS5A corroborated this observation in a quantitative manner. Interestingly, comparative NMR studies on two 20-mer NS5A peptides that contain D320 or E320 revealed a shift in population between the major and minor conformers. These data suggest that D320E conferred low-level resistance to DEB025 probably by reducing the need for CypA-dependent isomerisation of NS5A. Prolonged DEB025 treatment and multiple genotypic changes may be necessary to generate significant resistance to DEB025, underlying the high barrier to resistance.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2010-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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