54 results on '"Teulon JM"'
Search Results
2. Synthesis and aldose reductase inhibitory activity of N-(quinolinyl thiocarbonyl) glycine derivatives
- Author
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Nicolaï, E, primary, Güngör, T, additional, Goyard, J, additional, Cure, G, additional, Fouquet, A, additional, Teulon, JM, additional, Delchambre, C, additional, and Cloarec, A, additional
- Published
- 1992
- Full Text
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3. Synthesis and analgesic activities of urea derivatives of α-amino-N-pyridyl benzene propanamide
- Author
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Sartori, E, Camy, F, Teulon, JM, Camborde, F, Meignen, J, Hertz, F, and Cloarec, A
- Published
- 1994
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4. Synthesis and activities of new arylsulfonamido thromboxane A 2 receptor antagonists
- Author
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Sartori, E, Camy, F, Teulon, JM, Caussade, F, Virone-Oddos, A, and Cloarec, A
- Published
- 1993
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5. Correlation between plant cell wall stiffening and root extension arrest phenotype in the combined abiotic stress of Fe and Al.
- Author
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Kaur H, Teulon JM, Godon C, Desnos T, Chen SW, and Pellequer JL
- Subjects
- Malates, Plant Roots, Aluminum pharmacology, Cell Wall, Ions, Arabidopsis Proteins genetics, Arabidopsis
- Abstract
The plasticity and growth of plant cell walls (CWs) remain poorly understood at the molecular level. In this work, we used atomic force microscopy (AFM) to observe elastic responses of the root transition zone of 4-day-old Arabidopsis thaliana wild-type and almt1-mutant seedlings grown under Fe or Al stresses. Elastic parameters were deduced from force-distance curve measurements using the trimechanic-3PCS framework. The presence of single metal species Fe
2+ or Al3+ at 10 µM exerts no noticeable effect on the root growth compared with the control conditions. On the contrary, a mix of both the metal ions produced a strong root-extension arrest concomitant with significant increase of CW stiffness. Raising the concentration of either Fe2+ or Al3+ to 20 µM, no root-extension arrest was observed; nevertheless, an increase in root stiffness occurred. In the presence of both the metal ions at 10 µM, root-extension arrest was not observed in the almt1 mutant, which substantially abolishes the ability to exude malate. Our results indicate that the combination of Fe2+ and Al3+ with exuded malate is crucial for both CW stiffening and root-extension arrest. However, stiffness increase induced by single Fe2+ or Al3+ is not sufficient for arresting root growth in our experimental conditions., (© 2023 The Authors. Plant, Cell & Environment published by John Wiley & Sons Ltd.)- Published
- 2024
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6. Cryo-EM structure of influenza helical nucleocapsid reveals NP-NP and NP-RNA interactions as a model for the genome encapsidation.
- Author
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Chenavier F, Estrozi LF, Teulon JM, Zarkadas E, Freslon LL, Pellequer JL, Ruigrok RWH, Schoehn G, Ballandras-Colas A, and Crépin T
- Subjects
- Humans, Cryoelectron Microscopy, Ribonucleoproteins genetics, RNA, Viral metabolism, Nucleocapsid metabolism, Nucleoproteins chemistry, Influenza, Human
- Abstract
Influenza virus genome encapsidation is essential for the formation of a helical viral ribonucleoprotein (vRNP) complex composed of nucleoproteins (NP), the trimeric polymerase, and the viral genome. Although low-resolution vRNP structures are available, it remains unclear how the viral RNA is encapsidated and how NPs assemble into the helical filament specific of influenza vRNPs. In this study, we established a biological tool, the RNP-like particles assembled from recombinant influenza A virus NP and synthetic RNA, and we present the first subnanometric cryo-electron microscopy structure of the helical NP-RNA complex (8.7 to 5.3 Å). The helical RNP-like structure reveals a parallel double-stranded conformation, allowing the visualization of NP-NP and NP-RNA interactions. The RNA, located at the interface of neighboring NP protomers, interacts with conserved residues previously described as essential for the NP-RNA interaction. The NP undergoes conformational changes to enable RNA binding and helix formation. Together, our findings provide relevant insights for understanding the mechanism for influenza genome encapsidation.
- Published
- 2023
- Full Text
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7. Cry11Aa and Cyt1Aa exhibit different structural orders in crystal topography.
- Author
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Chen SW, Teulon JM, and Pellequer JL
- Subjects
- Bacillus thuringiensis Toxins, Hemolysin Proteins chemistry, Hemolysin Proteins toxicity, Bacterial Proteins chemistry, Endotoxins chemistry, Endotoxins toxicity, Bacillus thuringiensis chemistry
- Abstract
Cry11Aa and Cyt1Aa are two pesticidal toxins produced by Bacillus thuringiensis subsp. israelensis. To improve our understanding of the nature of their oligomers in the toxic actions and synergistic effects, we performed the atomic force microscopy to probe the surfaces of their natively grown crystals, and used the L-weight filter to enhance the structural features. By L-weight filtering, molecular sizes of the Cry11Aa and Cyt1Aa monomers obtained are in excellent agreement with the three-dimensional structures determined by x-ray crystallography. Moreover, our results show that the layered feature of a structural element distinguishes the topographic characteristics of Cry11Aa and Cyt1Aa crystals, suggesting that the Cry11Aa toxin has a better chance than Cyt1Aa for multimerization and therefore cooperativeness of the toxic actions., (© 2023 The Authors. Journal of Molecular Recognition published by John Wiley & Sons Ltd.)
- Published
- 2023
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8. Measuring external primary cell wall elasticity of seedling roots using atomic force microscopy.
- Author
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Kaur H, Teulon JM, Foucher AE, Fenel D, Chen SW, Godon C, Desnos T, and Pellequer JL
- Abstract
Stiffness plays a central action in plant cell extension. Here, we present a protocol to detect changes in stiffness on the external epidermal cell wall of living plant roots using atomic force microscopy (AFM). We provide generalized instructions for collecting force-distance curves and analysis of stiffness using contact-based mechanical model. With this protocol, and some initial training in AFM, a user is able to perform indentation experiments on 4- and 5-day-old Arabidopsis thaliana and determine stiffness properties. For complete details on the use and execution of this protocol, please refer to Godon et al.
1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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9. Nano-structural stiffness measure for soft biomaterials of heterogeneous elasticity.
- Author
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Chen SW, Teulon JM, Kaur H, Godon C, and Pellequer JL
- Subjects
- Elasticity, Elastic Modulus, Microscopy, Atomic Force methods, Biocompatible Materials
- Abstract
Measuring the structural stiffness aims to reveal the impact of nanostructured components or various physiological circumstances on the elastic response of material to an external indentation. With a pyramidal tip at a nano-scale, we employed the atomic force microscopy (AFM) to indent the surfaces of two compositions of polyacrylamide gels with different softness and seedling roots of Arabidopsis thaliana . We found that the stiffness-depth curve derived from the measured force exhibits a heterogeneous character in elasticity. According to the tendency of stiffness-depth curve, we decomposed the responding force into depth-impact ( F
C ), Hookean ( FH ) and tip-shape ( FS ) components, called trimechanic, where FS and its gradient should be offset at the surface or subsurfaces of the indented material. Thereby, trimechnic theory allows us to observe how the three restoring nanomechanics change with varied depth. Their strengths are represented by the respective spring constants ( kC , kH , kS ) of three parallel-connected spring (3PCS) analogs to differentiate restoring nanomechansims of indented materials. The effective Young's modulus Ê and the total stiffness kT (= kH + kS ) globally unambiguously distinguish the softness between the two gel categories. Data fluctuations were observed in the elasticity parameters of individual samples, reflecting nanostructural variations in the gel matrix. Similar tendencies were found in the results from growing plant roots, though the data fluctuations are expectedly much more dramatic. The zone-wise representation of stiffness by the trimechanic-3PCS framework demonstrates a stiffness measure that reflects beneath nanostructures encountered by deepened depth. The trimechanic-3PCS framework can apply any mechanical model of power-law based force-depth relationship and is compatible with thin layer corrections. It provides a new paradigm for analyzing restoring nanomechanics of soft biomaterials in response to indenting forces.- Published
- 2022
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10. De novo determination of mosquitocidal Cry11Aa and Cry11Ba structures from naturally-occurring nanocrystals.
- Author
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Tetreau G, Sawaya MR, De Zitter E, Andreeva EA, Banneville AS, Schibrowsky NA, Coquelle N, Brewster AS, Grünbein ML, Kovacs GN, Hunter MS, Kloos M, Sierra RG, Schiro G, Qiao P, Stricker M, Bideshi D, Young ID, Zala N, Engilberge S, Gorel A, Signor L, Teulon JM, Hilpert M, Foucar L, Bielecki J, Bean R, de Wijn R, Sato T, Kirkwood H, Letrun R, Batyuk A, Snigireva I, Fenel D, Schubert R, Canfield EJ, Alba MM, Laporte F, Després L, Bacia M, Roux A, Chapelle C, Riobé F, Maury O, Ling WL, Boutet S, Mancuso A, Gutsche I, Girard E, Barends TRM, Pellequer JL, Park HW, Laganowsky AD, Rodriguez J, Burghammer M, Shoeman RL, Doak RB, Weik M, Sauter NK, Federici B, Cascio D, Schlichting I, and Colletier JP
- Subjects
- Animals, Bacterial Proteins toxicity, Endotoxins, Hemolysin Proteins toxicity, Larva, Mosquito Control, Bacillus thuringiensis, Nanoparticles
- Abstract
Cry11Aa and Cry11Ba are the two most potent toxins produced by mosquitocidal Bacillus thuringiensis subsp. israelensis and jegathesan, respectively. The toxins naturally crystallize within the host; however, the crystals are too small for structure determination at synchrotron sources. Therefore, we applied serial femtosecond crystallography at X-ray free electron lasers to in vivo-grown nanocrystals of these toxins. The structure of Cry11Aa was determined de novo using the single-wavelength anomalous dispersion method, which in turn enabled the determination of the Cry11Ba structure by molecular replacement. The two structures reveal a new pattern for in vivo crystallization of Cry toxins, whereby each of their three domains packs with a symmetrically identical domain, and a cleavable crystal packing motif is located within the protoxin rather than at the termini. The diversity of in vivo crystallization patterns suggests explanations for their varied levels of toxicity and rational approaches to improve these toxins for mosquito control., (© 2022. The Author(s).)
- Published
- 2022
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11. Structural and functional characterization of DdrC, a novel DNA damage-induced nucleoid associated protein involved in DNA compaction.
- Author
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Banneville AS, Bouthier de la Tour C, De Bonis S, Hognon C, Colletier JP, Teulon JM, Le Roy A, Pellequer JL, Monari A, Dehez F, Confalonieri F, Servant P, and Timmins J
- Subjects
- Bacterial Proteins metabolism, DNA Damage, DNA Repair, DNA, Circular metabolism, Bacterial Proteins chemistry, Deinococcus genetics, Deinococcus metabolism
- Abstract
Deinococcus radiodurans is a spherical bacterium well-known for its outstanding resistance to DNA-damaging agents. Exposure to such agents leads to drastic changes in the transcriptome of D. radiodurans. In particular, four Deinococcus-specific genes, known as DNA Damage Response genes, are strongly up-regulated and have been shown to contribute to the resistance phenotype of D. radiodurans. One of these, DdrC, is expressed shortly after exposure to γ-radiation and is rapidly recruited to the nucleoid. In vitro, DdrC has been shown to compact circular DNA, circularize linear DNA, anneal complementary DNA strands and protect DNA from nucleases. To shed light on the possible functions of DdrC in D. radiodurans, we determined the crystal structure of the domain-swapped DdrC dimer at a resolution of 2.5 Å and further characterized its DNA binding and compaction properties. Notably, we show that DdrC bears two asymmetric DNA binding sites located on either side of the dimer and can modulate the topology and level of compaction of circular DNA. These findings suggest that DdrC may be a DNA damage-induced nucleoid-associated protein that enhances nucleoid compaction to limit the dispersion of the fragmented genome and facilitate DNA repair after exposure to severe DNA damaging conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2022
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12. Intrinsically Disordered Tardigrade Proteins Self-Assemble into Fibrous Gels in Response to Environmental Stress.
- Author
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Malki A, Teulon JM, Camacho-Zarco AR, Chen SW, Adamski W, Maurin D, Salvi N, Pellequer JL, and Blackledge M
- Subjects
- Animals, Gels chemistry, Intrinsically Disordered Proteins chemistry, Stress, Physiological, Tardigrada, Intrinsically Disordered Proteins chemical synthesis
- Abstract
Tardigrades are remarkable for their ability to survive harsh stress conditions as diverse as extreme temperature and desiccation. The molecular mechanisms that confer this unusual resistance to physical stress remain unknown. Recently, tardigrade-unique intrinsically disordered proteins have been shown to play an essential role in tardigrade anhydrobiosis. Here, we characterize the conformational and physical behaviour of CAHS-8 from Hypsibius exemplaris. NMR spectroscopy reveals that the protein comprises an extended central helical domain flanked by disordered termini. Upon concentration, the protein is shown to successively form oligomers, long fibres, and finally gels constituted of fibres in a strongly temperature-dependent manner. The helical domain forms the core of the fibrillar structure, with the disordered termini remaining highly dynamic within the gel. Soluble proteins can be encapsulated within cavities in the gel, maintaining their functional form. The ability to reversibly form fibrous gels may be associated with the enhanced protective properties of these proteins., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
- Published
- 2022
- Full Text
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13. The solid state of anti-inflammatory morniflumate diniflumate: A cocrystalline salt.
- Author
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Barrio M, Ceolin R, Robert B, Allouchi H, Teulon JM, Guéchot C, Tamarit JL, and Rietveld IB
- Subjects
- Calorimetry, Differential Scanning, Molecular Conformation, Anti-Inflammatory Agents, Niflumic Acid analogs & derivatives
- Abstract
Morniflumate diniflumate, a molecular compound involving niflumic acid and its β-morpholino ethyl ester (morniflumate) in the mole ratio 2:1, is found to crystallize in a triclinic P - 1 space group with a unit-cell volume of 2203.4(5) Å
3 . It is a cocrystal between a morniflumate+ niflumate- salt and a neutral niflumic acid molecule. The co-crystalline salt forms endothermically with a positive excess volume and it melts incongruently at 382.3(8) K. Differential scanning calorimetry executed at heating rates above 20 K⋅min-1 , leads to congruent melting at 387.8(9)K with an enthalpy change of Δfus H = 80(2) J g-1 . The rare occurrence that incongruent and congruent melting can be observed for the same cocrystal may be due to the conformational versatility of the niflumic acid molecule and its slow conversion between the different conformations due to weak intramolecular hydrogen bonding., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
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14. Insertion and activation of functional Bacteriorhodopsin in a floating bilayer.
- Author
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Mukhina T, Gerelli Y, Hemmerle A, Koutsioubas A, Kovalev K, Teulon JM, Pellequer JL, Daillant J, Charitat T, and Fragneto G
- Subjects
- Lipid Bilayers, Neutrons, Quartz Crystal Microbalance Techniques, Bacteriorhodopsins
- Abstract
The proton pump transmembrane protein bacteriorhodopsin was successfully incorporated into planar floating lipid bilayers in gel and fluid phases, by applying a detergent-mediated incorporation method. The method was optimized on single supported bilayers by using quartz crystal microbalance, atomic force and fluorescence microscopy techniques. Neutron and X-ray reflectometry were used on both single and floating bilayers with the aim of determining the structure and composition of this membrane-protein system before and after protein reconstitution at sub-nanometer resolution. Lipid bilayer integrity and protein activity were preserved upon the reconstitution process. Reversible structural modifications of the membrane, induced by the bacteriorhodopsin functional activity triggered by visible light, were observed and characterized at the nanoscale., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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15. Nanoscale surface structures of DNA bound to Deinococcus radiodurans HU unveiled by atomic force microscopy.
- Author
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Chen SW, Banneville AS, Teulon JM, Timmins J, and Pellequer JL
- Subjects
- Bacterial Proteins, DNA, DNA-Binding Proteins, Microscopy, Atomic Force, Deinococcus genetics
- Abstract
The Deinococcus radiodurans protein HU (DrHU) was shown to be critical for nucleoid activities, yet its functional and structural properties remain largely unexplored. We have applied atomic force microscopy (AFM) imaging to study DrHU binding to pUC19-DNA in vitro and analyzed the topographic structures formed at the nanoscale. At the single-molecule level, AFM imaging allows visualization of super-helical turns on naked DNA surfaces and characterization of free DrHU molecules observed as homodimers. When enhancing the molecular surface structures of AFM images by the Laplacian weight filter, the distribution of bound DrHUs was visibly varied as a function of the DrHU/DNA molar ratio. At a low molar ratio, DrHU binding was found to reduce the volume of condensed DNA configuration by about 50%. We also show that DrHU is capable of bridging distinct DNA segments. Moreover, at a low molar ratio, the binding orientation of individual DrHU dimers could be perceived on partially "open" DNA configuration. At a high molar ratio, DrHU stiffened the DNA molecule and enlarged the spread of the open DNA configuration. Furthermore, a lattice-like pattern could be seen on the surface of DrHU-DNA complex, indicating that DrHU multimerization had occurred leading to the formation of a higher order architecture. Together, our results show that the functional plasticity of DrHU in mediating DNA organization is subject to both the conformational dynamics of DNA molecules and protein abundance.
- Published
- 2020
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16. Exolysin (ExlA) from Pseudomonas aeruginosa Punctures Holes into Target Membranes Using a Molten Globule Domain.
- Author
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Bertrand Q, Job V, Maillard AP, Imbert L, Teulon JM, Favier A, Pellequer JL, Huber P, Attrée I, and Dessen A
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- A549 Cells, Bacterial Toxins genetics, Bacterial Translocation, Humans, Magnetic Resonance Spectroscopy, Microscopy, Atomic Force, Mutation, Protein Domains, Pseudomonas aeruginosa metabolism, Scattering, Small Angle, Virulence, X-Ray Diffraction, Bacterial Toxins chemistry, Bacterial Toxins metabolism, Membrane Microdomains metabolism, Pseudomonas aeruginosa pathogenicity
- Abstract
Bacteria employ several mechanisms, and most notably secretion systems, to translocate effectors from the cytoplasm to the extracellular environment or the cell surface. Pseudomonas aeruginosa widely employs secretion machineries such as the Type III Secretion System to support virulence and cytotoxicity. However, recently identified P. aeruginosa strains that do not express the Type III Secretion System have been shown to express ExlA, an exolysin translocated through a two-partner secretion system, and are the causative agents of severe lung hemorrhage. Sequence predictions of ExlA indicate filamentous hemagglutinin (FHA-2) domains as the prevalent features, followed by a C-terminal domain with no known homologs. In this work, we have addressed the mechanism employed by ExlA to target membrane bilayers by using NMR, small-angle X-ray scattering, atomic force microscopy, and cellular infection techniques. We show that the C-terminal domain of ExlA displays a "molten globule-like" fold that punctures small holes into membranes composed of negatively charged lipids, while other domains could play a lesser role in target recognition. In addition, epithelial cells infected with P. aeruginosa strains expressing different ExlA variants allow localization of the toxin to lipid rafts. ExlA homologs have been identified in numerous bacterial strains, indicating that lipid bilayer destruction is an effective strategy employed by bacteria to establish interactions with multiple hosts., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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17. Visualizing the functional 3D shape and topography of long noncoding RNAs by single-particle atomic force microscopy and in-solution hydrodynamic techniques.
- Author
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Uroda T, Chillón I, Annibale P, Teulon JM, Pessey O, Karuppasamy M, Pellequer JL, and Marcia M
- Subjects
- Image Processing, Computer-Assisted, Hydrodynamics, Microscopy, Atomic Force methods, RNA, Long Noncoding chemistry
- Abstract
Long noncoding RNAs (lncRNAs) are recently discovered transcripts that regulate vital cellular processes, such as cellular differentiation and DNA replication, and are crucially connected to diseases. Although the 3D structures of lncRNAs are key determinants of their function, the unprecedented molecular complexity of lncRNAs has so far precluded their 3D structural characterization at high resolution. It is thus paramount to develop novel approaches for biochemical and biophysical characterization of these challenging targets. Here, we present a protocol that integrates non-denaturing lncRNA purification with in-solution hydrodynamic analysis and single-particle atomic force microscopy (AFM) imaging to produce highly homogeneous lncRNA preparations and visualize their 3D topology at ~15-Å resolution. Our protocol is suitable for imaging lncRNAs in biologically active conformations and for measuring structural defects of functionally inactive mutants that have been identified by cell-based functional assays. Once optimized for the specific target lncRNA of choice, our protocol leads from cloning to AFM imaging within 3-4 weeks and can be implemented using state-of-the-art biochemical and biophysical instrumentation by trained researchers familiar with RNA handling and supported by AFM and small-angle X-ray scattering (SAXS) experts.
- Published
- 2020
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18. Serial femtosecond crystallography on in vivo-grown crystals drives elucidation of mosquitocidal Cyt1Aa bioactivation cascade.
- Author
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Tetreau G, Banneville AS, Andreeva EA, Brewster AS, Hunter MS, Sierra RG, Teulon JM, Young ID, Burke N, Grünewald TA, Beaudouin J, Snigireva I, Fernandez-Luna MT, Burt A, Park HW, Signor L, Bafna JA, Sadir R, Fenel D, Boeri-Erba E, Bacia M, Zala N, Laporte F, Després L, Weik M, Boutet S, Rosenthal M, Coquelle N, Burghammer M, Cascio D, Sawaya MR, Winterhalter M, Gratton E, Gutsche I, Federici B, Pellequer JL, Sauter NK, and Colletier JP
- Subjects
- Animals, Bacillus thuringiensis Toxins, Bacterial Proteins genetics, Bacterial Proteins pharmacology, Cell Membrane drug effects, Crystallography, X-Ray, Disulfides chemistry, Endotoxins genetics, Endotoxins pharmacology, HEK293 Cells, Hemolysin Proteins genetics, Hemolysin Proteins pharmacology, Humans, Hydrogen-Ion Concentration, Insecticides chemistry, Insecticides metabolism, Insecticides pharmacology, Mice, Microscopy, Atomic Force, NIH 3T3 Cells, Protein Conformation, Sf9 Cells, Bacterial Proteins chemistry, Bacterial Proteins metabolism, Endotoxins chemistry, Endotoxins metabolism, Hemolysin Proteins chemistry, Hemolysin Proteins metabolism
- Abstract
Cyt1Aa is the one of four crystalline protoxins produced by mosquitocidal bacterium Bacillus thuringiensis israelensis (Bti) that has been shown to delay the evolution of insect resistance in the field. Limiting our understanding of Bti efficacy and the path to improved toxicity and spectrum has been ignorance of how Cyt1Aa crystallizes in vivo and of its mechanism of toxicity. Here, we use serial femtosecond crystallography to determine the Cyt1Aa protoxin structure from sub-micron-sized crystals produced in Bti. Structures determined under various pH/redox conditions illuminate the role played by previously uncharacterized disulfide-bridge and domain-swapped interfaces from crystal formation in Bti to dissolution in the larval mosquito midgut. Biochemical, toxicological and biophysical methods enable the deconvolution of key steps in the Cyt1Aa bioactivation cascade. We additionally show that the size, shape, production yield, pH sensitivity and toxicity of Cyt1Aa crystals grown in Bti can be controlled by single atom substitution.
- Published
- 2020
- Full Text
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19. Conserved Pseudoknots in lncRNA MEG3 Are Essential for Stimulation of the p53 Pathway.
- Author
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Uroda T, Anastasakou E, Rossi A, Teulon JM, Pellequer JL, Annibale P, Pessey O, Inga A, Chillón I, and Marcia M
- Subjects
- HCT116 Cells, Humans, RNA Folding, RNA, Long Noncoding genetics, Tumor Suppressor Protein p53 genetics, Genes, Tumor Suppressor, Nucleotide Motifs, RNA, Long Noncoding metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Long non-coding RNAs (lncRNAs) are key regulatory molecules, but unlike with other RNAs, the direct link between their tertiary structure motifs and their function has proven elusive. Here we report structural and functional studies of human maternally expressed gene 3 (MEG3), a tumor suppressor lncRNA that modulates the p53 response. We found that, in an evolutionary conserved region of MEG3, two distal motifs interact by base complementarity to form alternative, mutually exclusive pseudoknot structures ("kissing loops"). Mutations that disrupt these interactions impair MEG3-dependent p53 stimulation in vivo and disrupt MEG3 folding in vitro. These findings provide mechanistic insights into regulation of the p53 pathway by MEG3 and reveal how conserved motifs of tertiary structure can regulate lncRNA biological function., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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20. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death.
- Author
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Silvestre-Roig C, Braster Q, Wichapong K, Lee EY, Teulon JM, Berrebeh N, Winter J, Adrover JM, Santos GS, Froese A, Lemnitzer P, Ortega-Gómez A, Chevre R, Marschner J, Schumski A, Winter C, Perez-Olivares L, Pan C, Paulin N, Schoufour T, Hartwig H, González-Ramos S, Kamp F, Megens RTA, Mowen KA, Gunzer M, Maegdefessel L, Hackeng T, Lutgens E, Daemen M, von Blume J, Anders HJ, Nikolaev VO, Pellequer JL, Weber C, Hidalgo A, Nicolaes GAF, Wong GCL, and Soehnlein O
- Subjects
- Animals, Arteries pathology, Cell Membrane drug effects, Disease Models, Animal, Female, Histones antagonists & inhibitors, Mice, Mice, Inbred C57BL, Myocytes, Smooth Muscle pathology, Neutrophils cytology, Protein Binding drug effects, Atherosclerosis pathology, Cell Death, Cell Membrane metabolism, Histones metabolism, Inflammation metabolism, Inflammation pathology, Porosity
- Abstract
The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death
1,2 ; however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis-a major underlying cause of mortality worldwide-to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.- Published
- 2019
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21. Structural and Functional Characterization of the Type Three Secretion System (T3SS) Needle of Pseudomonas aeruginosa .
- Author
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Lombardi C, Tolchard J, Bouillot S, Signor L, Gebus C, Liebl D, Fenel D, Teulon JM, Brock J, Habenstein B, Pellequer JL, Faudry E, Loquet A, Attrée I, Dessen A, and Job V
- Abstract
The type three secretion system (T3SS) is a macromolecular protein nano-syringe used by different bacterial pathogens to inject effectors into host cells. The extracellular part of the syringe is a needle-like filament formed by the polymerization of a 9-kDa protein whose structure and proper localization on the bacterial surface are key determinants for efficient toxin injection. Here, we combined in vivo , in vitro , and in silico approaches to characterize the Pseudomonas aeruginosa T3SS needle and its major component PscF. Using a combination of mutagenesis, phenotypic analyses, immunofluorescence, proteolysis, mass spectrometry, atomic force microscopy, electron microscopy, and molecular modeling, we propose a model of the P. aeruginosa needle that exposes the N-terminal region of each PscF monomer toward the outside of the filament, while the core of the fiber is formed by the C-terminal helix. Among mutations introduced into the needle protein PscF, D76A, and P47A/Q54A caused a defect in the assembly of the needle on the bacterial surface, although the double mutant was still cytotoxic on macrophages in a T3SS-dependent manner and formed filamentous structures in vitro . These results suggest that the T3SS needle of P. aeruginosa displays an architecture that is similar to that of other bacterial needles studied to date and highlight the fact that small, targeted perturbations in needle assembly can inhibit T3SS function. Therefore, the T3SS needle represents an excellent drug target for small molecules acting as virulence blockers that could disrupt pathogenesis of a broad range of bacteria.
- Published
- 2019
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22. On the Operational Aspects of Measuring Nanoparticle Sizes.
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Teulon JM, Godon C, Chantalat L, Moriscot C, Cambedouzou J, Odorico M, Ravaux J, Podor R, Gerdil A, Habert A, Herlin-Boime N, Chen SW, and Pellequer JL
- Abstract
Nanoparticles are defined as elementary particles with a size between 1 and 100 nm for at least 50% (in number). They can be made from natural materials, or manufactured. Due to their small sizes, novel toxicological issues are raised and thus determining the accurate size of these nanoparticles is a major challenge. In this study, we performed an intercomparison experiment with the goal to measure sizes of several nanoparticles, in a first step, calibrated beads and monodispersed SiO₂ Ludox®, and, in a second step, nanoparticles (NPs) of toxicological interest, such as Silver NM-300 K and PVP-coated Ag NPs, Titanium dioxide A12, P25(Degussa), and E171(A), using commonly available laboratory techniques such as transmission electron microscopy, scanning electron microscopy, small-angle X-ray scattering, dynamic light scattering, wet scanning transmission electron microscopy (and its dry state, STEM) and atomic force microscopy. With monomodal distributed NPs (polystyrene beads and SiO₂ Ludox®), all tested techniques provide a global size value amplitude within 25% from each other, whereas on multimodal distributed NPs (Ag and TiO₂) the inter-technique variation in size values reaches 300%. Our results highlight several pitfalls of NP size measurements such as operational aspects, which are unexpected consequences in the choice of experimental protocols. It reinforces the idea that averaging the NP size from different biophysical techniques (and experimental protocols) is more robust than focusing on repetitions of a single technique. Besides, when characterizing a heterogeneous NP in size, a size distribution is more informative than a simple average value. This work emphasizes the need for nanotoxicologists (and regulatory agencies) to test a large panel of different techniques before making a choice for the most appropriate technique(s)/protocol(s) to characterize a peculiar NP.
- Published
- 2018
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23. Standardized Nanomechanical Atomic Force Microscopy Procedure (SNAP) for Measuring Soft and Biological Samples.
- Author
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Schillers H, Rianna C, Schäpe J, Luque T, Doschke H, Wälte M, Uriarte JJ, Campillo N, Michanetzis GPA, Bobrowska J, Dumitru A, Herruzo ET, Bovio S, Parot P, Galluzzi M, Podestà A, Puricelli L, Scheuring S, Missirlis Y, Garcia R, Odorico M, Teulon JM, Lafont F, Lekka M, Rico F, Rigato A, Pellequer JL, Oberleithner H, Navajas D, and Radmacher M
- Subjects
- Animals, Dogs, Elastic Modulus, Madin Darby Canine Kidney Cells, Nanotechnology, Reproducibility of Results, Stress, Mechanical, Hydrogels chemistry, Microscopy, Atomic Force methods
- Abstract
We present a procedure that allows a reliable determination of the elastic (Young's) modulus of soft samples, including living cells, by atomic force microscopy (AFM). The standardized nanomechanical AFM procedure (SNAP) ensures the precise adjustment of the AFM optical lever system, a prerequisite for all kinds of force spectroscopy methods, to obtain reliable values independent of the instrument, laboratory and operator. Measurements of soft hydrogel samples with a well-defined elastic modulus using different AFMs revealed that the uncertainties in the determination of the deflection sensitivity and subsequently cantilever's spring constant were the main sources of error. SNAP eliminates those errors by calculating the correct deflection sensitivity based on spring constants determined with a vibrometer. The procedure was validated within a large network of European laboratories by measuring the elastic properties of gels and living cells, showing that its application reduces the variability in elastic moduli of hydrogels down to 1%, and increased the consistency of living cells elasticity measurements by a factor of two. The high reproducibility of elasticity measurements provided by SNAP could improve significantly the applicability of cell mechanics as a quantitative marker to discriminate between cell types and conditions.
- Published
- 2017
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24. Low phosphate activates STOP1-ALMT1 to rapidly inhibit root cell elongation.
- Author
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Balzergue C, Dartevelle T, Godon C, Laugier E, Meisrimler C, Teulon JM, Creff A, Bissler M, Brouchoud C, Hagège A, Müller J, Chiarenza S, Javot H, Becuwe-Linka N, David P, Péret B, Delannoy E, Thibaud MC, Armengaud J, Abel S, Pellequer JL, Nussaume L, and Desnos T
- Subjects
- Arabidopsis genetics, Arabidopsis metabolism, Arabidopsis Proteins genetics, Cell Enlargement, Cell Wall genetics, Cell Wall metabolism, Gene Expression Regulation, Plant, Iron metabolism, Malates metabolism, Meristem cytology, Meristem genetics, Meristem metabolism, Organic Anion Transporters genetics, Oxidoreductases genetics, Oxidoreductases metabolism, Peroxidase genetics, Peroxidase metabolism, Plant Roots cytology, Plant Roots genetics, Plants, Genetically Modified, Signal Transduction genetics, Transcription Factors genetics, Arabidopsis Proteins metabolism, Organic Anion Transporters metabolism, Phosphates metabolism, Plant Roots metabolism, Transcription Factors metabolism
- Abstract
Environmental cues profoundly modulate cell proliferation and cell elongation to inform and direct plant growth and development. External phosphate (Pi) limitation inhibits primary root growth in many plant species. However, the underlying Pi sensory mechanisms are unknown. Here we genetically uncouple two Pi sensing pathways in the root apex of Arabidopsis thaliana. First, the rapid inhibition of cell elongation in the transition zone is controlled by transcription factor STOP1, by its direct target, ALMT1, encoding a malate channel, and by ferroxidase LPR1, which together mediate Fe and peroxidase-dependent cell wall stiffening. Second, during the subsequent slow inhibition of cell proliferation in the apical meristem, which is mediated by LPR1-dependent, but largely STOP1-ALMT1-independent, Fe and callose accumulate in the stem cell niche, leading to meristem reduction. Our work uncovers STOP1 and ALMT1 as a signalling pathway of low Pi availability and exuded malate as an unexpected apoplastic inhibitor of root cell wall expansion.
- Published
- 2017
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25. Conditions to minimize soft single biomolecule deformation when imaging with atomic force microscopy.
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Godon C, Teulon JM, Odorico M, Basset C, Meillan M, Vellutini L, Chen SW, and Pellequer JL
- Subjects
- Tobacco Mosaic Virus ultrastructure, Microscopy, Atomic Force methods
- Abstract
A recurrent interrogation when imaging soft biomolecules using atomic force microscopy (AFM) is the putative deformation of molecules leading to a bias in recording true topographical surfaces. Deformation of biomolecules comes from three sources: sample instability, adsorption to the imaging substrate, and crushing under tip pressure. To disentangle these causes, we measured the maximum height of a well-known biomolecule, the tobacco mosaic virus (TMV), under eight different experimental conditions positing that the maximum height value is a specific indicator of sample deformations. Six basic AFM experimental factors were tested: imaging in air (AIR) versus in liquid (LIQ), imaging with flat minerals (MICA) versus flat organic surfaces (self-assembled monolayers, SAM), and imaging forces with oscillating tapping mode (TAP) versus PeakForce tapping (PFT). The results show that the most critical parameter in accurately measuring the height of TMV in air is the substrate. In a liquid environment, regardless of the substrate, the most critical parameter is the imaging mode. Most importantly, the expected TMV height values were obtained with both imaging with the PeakForce tapping mode either in liquid or in air at the condition of using self-assembled monolayers as substrate. This study unambiguously explains previous poor results of imaging biomolecules on mica in air and suggests alternative methodologies for depositing soft biomolecules on well organized self-assembled monolayers., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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26. Combined small angle X-ray solution scattering with atomic force microscopy for characterizing radiation damage on biological macromolecules.
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Costa L, Andriatis A, Brennich M, Teulon JM, Chen SW, Pellequer JL, and Round A
- Subjects
- Amylases metabolism, Amylases radiation effects, Ipomoea batatas enzymology, Nickel chemistry, Protein Structure, Quaternary, Tobacco Mosaic Virus chemistry, Tobacco Mosaic Virus radiation effects, X-Ray Diffraction, X-Rays, Amylases chemistry, Microscopy, Atomic Force, Scattering, Small Angle
- Abstract
Background: Synchrotron radiation facilities are pillars of modern structural biology. Small-Angle X-ray scattering performed at synchrotron sources is often used to characterize the shape of biological macromolecules. A major challenge with high-energy X-ray beam on such macromolecules is the perturbation of sample due to radiation damage., Results: By employing atomic force microscopy, another common technique to determine the shape of biological macromolecules when deposited on flat substrates, we present a protocol to evaluate and characterize consequences of radiation damage. It requires the acquisition of images of irradiated samples at the single molecule level in a timely manner while using minimal amounts of protein. The protocol has been tested on two different molecular systems: a large globular tetremeric enzyme (β-Amylase) and a rod-shape plant virus (tobacco mosaic virus). Radiation damage on the globular enzyme leads to an apparent increase in molecular sizes whereas the effect on the long virus is a breakage into smaller pieces resulting in a decrease of the average long-axis radius., Conclusions: These results show that radiation damage can appear in different forms and strongly support the need to check the effect of radiation damage at synchrotron sources using the presented protocol.
- Published
- 2016
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27. Atomic force microscope, molecular imaging, and analysis.
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Chen SW, Teulon JM, Godon C, and Pellequer JL
- Subjects
- Algorithms, Image Processing, Computer-Assisted methods, Tobacco Mosaic Virus chemistry, Microscopy, Atomic Force methods, Proteins chemistry
- Abstract
Image visibility is a central issue in analyzing all kinds of microscopic images. An increase of intensity contrast helps to raise the image visibility, thereby to reveal fine image features. Accordingly, a proper evaluation of results with current imaging parameters can be used for feedback on future imaging experiments. In this work, we have applied the Laplacian function of image intensity as either an additive component (Laplacian mask) or a multiplying factor (Laplacian weight) for enhancing image contrast of high-resolution AFM images of two molecular systems, an unknown protein imaged in air, provided by AFM COST Action TD1002 (http://www.afm4nanomedbio.eu/), and tobacco mosaic virus (TMV) particles imaged in liquid. Based on both visual inspection and quantitative representation of contrast measurements, we found that the Laplacian weight is more effective than the Laplacian mask for the unknown protein, whereas for the TMV system the strengthened Laplacian mask is superior to the Laplacian weight. The present results indicate that a mathematical function, as exemplified by the Laplacian function, may yield varied processing effects with different operations. To interpret the diversity of molecular structure and topology in images, an explicit expression for processing procedures should be included in scientific reports alongside instrumental setups., (Copyright © 2015 John Wiley & Sons, Ltd.)
- Published
- 2016
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28. Virus particle assembly into crystalline domains enabled by the coffee ring effect.
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Gebhardt R, Teulon JM, Pellequer JL, Burghammer M, Colletier JP, and Riekel C
- Subjects
- Crystallization, Microscopy, Atomic Force, X-Ray Diffraction, Tobacco Mosaic Virus chemistry, Virion chemistry
- Abstract
Tobacco mosaic virus particles can be rapidly assembled into 3D-domains by capillary flow-driven alignment at the triple contact-line of an evaporating droplet. Virus particles of ∼150 Å diameter can be resolved within individual domains at the outer rim of the "coffee-ring" type residue by atomic force microscopy. The crystalline domains can also be probed by X-ray microdiffraction techniques. Both techniques reveal that the rod-like virus particles are oriented parallel to the rim. We further demonstrate the feasibility of collection of hk0 reflection intensities in GISAXS geometry and show it allows calculating a low-resolution electron density projection along the rod axis.
- Published
- 2014
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29. Degradation pathways study of the natriuretic and β-adrenoceptor antagonist tienoxolol using liquid chromatography-electrospray ionization multistage mass spectrometry.
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Gana I, Dugay A, Henriet T, Rietveld IB, Bernard M, Guechot C, Teulon JM, Safta F, Yagoubi N, Céolin R, and Do B
- Subjects
- Adrenergic beta-Antagonists analysis, Adrenergic beta-Antagonists chemistry, Drug Stability, Drug Storage, Propanolamines chemistry, Tandem Mass Spectrometry methods, Chromatography, High Pressure Liquid methods, Propanolamines analysis, Spectrometry, Mass, Electrospray Ionization methods
- Abstract
Tienoxolol is a pharmacologically active molecule designed with the functional groups ketothiophene, alkyl benzoate and arylpropanolamine so as to combine a diuretic and a β-adrenoreceptor antagonist into a single molecule. Its degradation products generated in several stress media have been determined by high-pressure liquid chromatography (HPLC) coupled to a hybrid mass spectrometer with a triple quadrupole-linear trap. A Polaris(®) column with a C18-A stationary phase and a linear gradient mobile phase composed of a mixture of trifluoroacetic acid 1% (v/v) and acetonitrile allowed for optimal separation. Structural elucidation of the degradation products has been based on MS/MS techniques, by comparing their fragmentation patterns to the precursor's data. Up to seven degradation products of the active ingredient, resulting from hydrolysis, oxidation, dehydration and transamidation have been identified, covering a range of possible degradation pathways for derivatives with such functional groups. Kinetics have been studied to assess the molecule's shelf life and to identify the most important degradation factor., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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30. Nanoscale structural features determined by AFM for single virus particles.
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Chen SW, Odorico M, Meillan M, Vellutini L, Teulon JM, Parot P, Bennetau B, and Pellequer JL
- Subjects
- Algorithms, Surface Properties, Tobacco Mosaic Virus chemistry, Tobacco Mosaic Virus physiology, Microscopy, Atomic Force, Nanostructures chemistry, Virion isolation & purification
- Abstract
In this work, we propose "single-image analysis", as opposed to multi-image averaging, for extracting valuable information from AFM images of single bio-particles. This approach allows us to study molecular systems imaged by AFM under general circumstances without restrictions on their structural forms. As feature exhibition is a resolution correlation, we have performed AFM imaging on surfaces of tobacco mosaic virus (TMV) to demonstrate variations of structural patterns with probing resolution. Two AFM images were acquired with the same tip at different probing resolutions in terms of pixel width, i.e., 1.95 and 0.49 nm per pixel. For assessment, we have constructed an in silico topograph based on the three-dimensional crystal structure of TMV as a reference. The prominent artifacts observed in the AFM-determined shape of TMV were attributed to tip convolutions. The width of TMV rod was systematically overestimated by ~10 nm at both probing resolutions of AFM. Nevertheless, the effects of tip convolution were less severe in vertical orientation so that the estimated height of TMV by AFM imaging was in close agreement with the in silico X-ray topograph. Using dedicated image processing algorithms, we found that at low resolution (i.e., 1.95 nm per pixel), the extracted surface features of TMV can be interpreted as a partial or full helical repeat (three complete turns with ~7.0 nm in length), while individual protein subunits (~2.5 nm) were perceivable only at high resolution. The present study shows that the scales of revealed structural features in AFM images are subject to both probing resolution and processing algorithms for image analysis.
- Published
- 2013
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31. Conformational dynamics of individual antibodies using computational docking and AFM.
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Chaves RC, Teulon JM, Odorico M, Parot P, Chen SW, and Pellequer JL
- Subjects
- Imaging, Three-Dimensional, Immunoglobulin D chemistry, Immunoglobulin G chemistry, Protein Conformation, Antibodies chemistry, Microscopy, Atomic Force, Molecular Docking Simulation
- Abstract
Molecular recognition between a receptor and a ligand requires a certain level of flexibility in macromolecules. In this study, we aimed at analyzing the conformational variability of receptors portrayed by monoclonal antibodies that have been individually imaged using atomic force microscopy (AFM). Individual antibodies were chemically coupled to activated mica surface, and they have been imaged using AFM in ambient conditions. The resulting topographical surface of antibodies was used to assemble the three subunits constituting antibodies: two antigen-binding fragments and one crystallizable fragment using a surface-constrained computational docking approach. Reconstructed structures based on 10 individual topographical surfaces of antibodies are presented for which separation and relative orientation of the subunits were measured. When compared with three X-ray structures of antibodies present in the protein data bank database, results indicate that several arrangements of the reconstructed subunits are comparable with those of known structures. Nevertheless, no reconstructed structure superimposes adequately to any particular X-ray structure consequence of the antibody flexibility. We conclude that high-resolution AFM imaging with appropriate computational reconstruction tools is adapted to study the conformational dynamics of large individual macromolecules deposited on mica., (Copyright © 2013 John Wiley & Sons, Ltd.)
- Published
- 2013
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32. Crystal structure and solid-state studies of aged samples of tienoxolol, an API designed against hypertension.
- Author
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Mahé N, Do B, Nicolaï B, Rietveld IB, Barrio M, Tamarit JL, Céolin R, Guéchot C, and Teulon JM
- Subjects
- Calorimetry, Differential Scanning, Chemistry, Pharmaceutical, Chromatography, High Pressure Liquid, Crystallization, Crystallography, X-Ray, Drug Stability, Drug Storage, Humidity, Hydrolysis, Models, Molecular, Molecular Structure, Powder Diffraction, Spectrometry, Mass, Electrospray Ionization, Tandem Mass Spectrometry, Technology, Pharmaceutical methods, Temperature, Time Factors, Water chemistry, Antihypertensive Agents chemistry, Propanolamines chemistry
- Abstract
Aging of drug molecules is generally studied following regulatory procedures, i.e. under forced conditions and for relatively limited storage time; therefore naturally aged samples are rare and provide scientific reference data beyond regulatory considerations. Tienoxolol was studied after 25 years of storage in the dark under ambient conditions. About 86% of the samples still consisted of tienoxolol and the main impurity (13%) was caused by the hydrolysis of the ester moiety. Protection from humidity is therefore important. Other sensitive groups containing nitrogen and sulfur appear to be quite stable with less than 0.8% conversion over 25 years. In addition, the crystal structure has been solved. Tienoxolol orange needles were found to crystallize in the orthorhombic non-centrosymmetric space group Iba2, indicating that the crystal is a racemic compound. The unit cell parameters at room temperature are a=10.069(5)Å, b=45.831(10)Å, and c=9.822(5)Å and the unit cell volume is 4533(3)Å(3) with Z=8., (Copyright © 2011 Elsevier B.V. All rights reserved.)
- Published
- 2012
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33. Computational reconstruction of multidomain proteins using atomic force microscopy data.
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Trinh MH, Odorico M, Pique ME, Teulon JM, Roberts VA, Ten Eyck LF, Getzoff ED, Parot P, Chen SW, and Pellequer JL
- Subjects
- Aquaporins chemistry, Escherichia coli Proteins chemistry, Tobacco Mosaic Virus chemistry, Computational Biology methods, Microscopy, Atomic Force methods, Models, Molecular, Protein Structure, Tertiary, Proteins chemistry
- Abstract
Classical structural biology techniques face a great challenge to determine the structure at the atomic level of large and flexible macromolecules. We present a novel methodology that combines high-resolution AFM topographic images with atomic coordinates of proteins to assemble very large macromolecules or particles. Our method uses a two-step protocol: atomic coordinates of individual domains are docked beneath the molecular surface of the large macromolecule, and then each domain is assembled using a combinatorial search. The protocol was validated on three test cases: a simulated system of antibody structures; and two experimentally based test cases: Tobacco mosaic virus, a rod-shaped virus; and Aquaporin Z, a bacterial membrane protein. We have shown that AFM-intermediate resolution topography and partial surface data are useful constraints for building macromolecular assemblies. The protocol is applicable to multicomponent structures connected in the polypeptide chain or as disjoint molecules. The approach effectively increases the resolution of AFM beyond topographical information down to atomic-detail structures., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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34. Single and multiple bonds in (strept)avidin-biotin interactions.
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Teulon JM, Delcuze Y, Odorico M, Chen SW, Parot P, and Pellequer JL
- Subjects
- Microscopy, Atomic Force, Protein Binding, Streptavidin chemistry, Streptavidin metabolism, Avidin chemistry, Avidin metabolism, Biotin chemistry, Biotin metabolism
- Abstract
Thanks to Dynamic Force Spectroscopy (DFS) and developments of massive data analysis tools, such as YieldFinder, Atomic Force Microscopy (AFM) becomes a powerful method for analyzing long lifetime ligand-receptor interactions. We have chosen the well-known system, (strept)avidin-biotin complex, as an experimental model due to the lack of consensus on interpretations of the rupture force spectrum (Walton et al., 2008). We present new measurements of force-displacement curves for the (strept)avidin-biotin complex. These data were analyzed using the YieldFinder software based on the Bell-Evans formalism. In addition, the Williams model was adopted to interpret the bonding state of the system. Our results indicate the presence of at least two energy barriers in two loading rate regimes. Combining with structural analysis, the energy barriers can be interpreted in a novel physico-chemical context as one inner barrier for H-bond ruptures ( <1 Å), and one outer barrier for escaping from the binding pocket which is blocked by the side chain of a symmetry-related Trp120 in the streptavidin tetramer. In each loading rate regime, the presence of multiple parallel bonds was implied by the Williams model. Interestingly, we found that in literature different terms created for addressing the apparent discrepancies in the results of avidin-biotin interactions can be reconciled by taking into account multiple parallel bonds., (Copyright © 2011 John Wiley & Sons, Ltd.)
- Published
- 2011
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35. Deciphering the energy landscape of the interaction uranyl-DCP with antibodies using dynamic force spectroscopy.
- Author
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Teulon JM, Parot P, Odorico M, and Pellequer JL
- Subjects
- Binding Sites, Energy Transfer, Protein Binding, Protein Interaction Mapping methods, Antibodies, Monoclonal chemistry, Chelating Agents chemistry, Microscopy, Atomic Force methods, Phenanthrolines chemistry, Uranium Compounds chemistry
- Abstract
Previous studies on molecular recognition of uranyl-DCP (dicarboxy-phenanthroline chelator) compound by two distinct monoclonal antibodies (Mabs U04S and U08S) clearly showed the presence of a biphasic shape in Bell-Evans' plots and an accentuated difference in slopes at the high loading rates. To further explore the basis in the slope difference, we have performed complementary experiments using antibody PHE03S, raised against uranyl-DCP but, presenting a strong cross-reactivity toward the DCP chelator. This work allowed us to obtain a reallocation of the respective contributions of the metal ion itself and that of the chelator. Results led us to propose a 2D schematic model representing two energy barriers observed in the systems Mabs U04S- and U08S-[UO(2)-DCP] where the outer barrier characterizes the interaction between UO(2) and Mab whereas the inner barrier characterizes the interaction between DCP and Mab. Using dynamic force spectroscopy, it is thus possible to dissect molecular interactions during the unbinding between proteins and ligands.
- Published
- 2008
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36. On molecular recognition of an uranyl chelate by monoclonal antibodies.
- Author
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Teulon JM, Odorico M, Chen SW, Parot P, and Pellequer JL
- Subjects
- Antibodies, Monoclonal chemistry, Antibody Affinity, Antibody Specificity, Antigen-Antibody Reactions, Binding Sites, Antibody, Chelating Agents chemistry, Chelating Agents pharmacology, Hydrogen Bonding, Kinetics, Microscopy, Atomic Force, Models, Molecular, Phenanthrolines chemistry, Protein Binding, Uranium Compounds chemistry, Antibodies, Monoclonal metabolism, Phenanthrolines pharmacology, Uranium Compounds metabolism
- Abstract
The energy landscape of the uranyl (UO2) chelate dissociated from a monoclonal antibody U08S was investigated using dynamic force spectroscopy (DFS). The uranyl ion (UO2(2+)) is chelated with the ligand dicarboxy-phenanthroline (DCP). The monoclonal antibody U08S was raised against UO2-DCP and does not cross-react with DCP alone. The results of plotting the most probable force against the logarithm of the loading rate show two distinguished values of slopes of multiple fitting lines, as observed in our previous study on that system with monoclonal antibody U04S (Odorico et al., 2007a. Biophys. J. 93: 645-654.). It indicates an unbinding process undergoing at least two activation states. We have generated the histogram of unbinding events with respect to the composite stiffness of the complex between the protein and the uranyl compound. Combining the model of Bell and Evans with that of Williams, we have estimated the number of parallel bonds involved in the unbinding process and determined the value of stiffness for individual bonds. We propose that the uranyl compound binds to the two antibodies U04S and U0c at structurally equivalent locations and forms the interaction with similar coordination modes. In addition, the unbinding process goes through two steps; the first weakens the bonding of the central metal with AspL50 of the antibody and the second breaks other non-bonded interactions of the compound with the antibody., (Copyright (c) 2007 John Wiley & Sons, Ltd.)
- Published
- 2007
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37. An integrated methodology for data processing in dynamic force spectroscopy of ligand-receptor binding.
- Author
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Odorico M, Teulon JM, Berthoumieu O, Chen SW, Parot P, and Pellequer JL
- Subjects
- Calibration, Ligands, Phenanthrolines chemistry, Protein Binding, Spectrum Analysis, Uranium chemistry, Antibodies, Monoclonal chemistry, Electronic Data Processing methods, Microscopy, Atomic Force methods
- Abstract
Dynamic force spectroscopy (DFS), using atomic force microscopy (AFM), is a powerful tool to study ligand-receptor binding. The interaction mode of two binding partners is investigated by exploring stochastic behaviors of bond rupture events. However, to define a rupture event from force-distance measurements is not conclusive or unique in literature. To reveal the influence of event identification methods, we have developed an efficient protocol to manage tremendous amount of data by implementing different choices of peak selection from the force-distance curve. This data processing software simplifies routinely experimental procedures such as cantilever spring constant and force-distance curve calibrations, statistical treatments of data, and analysis distributions of rupture events. In the present work, we took available experimental data from a complex between a chelate metal compound and a monoclonal antibody as a study system.
- Published
- 2007
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38. Energy landscape of chelated uranyl: antibody interactions by dynamic force spectroscopy.
- Author
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Odorico M, Teulon JM, Bessou T, Vidaud C, Bellanger L, Chen SW, Quéméneur E, Parot P, and Pellequer JL
- Subjects
- Binding Sites, Biophysical Phenomena, Biophysics, Chelating Agents, In Vitro Techniques, Microscopy, Atomic Force, Models, Molecular, Phenanthrolines chemistry, Protein Conformation, Thermodynamics, Antibodies, Monoclonal chemistry, Uranium chemistry
- Abstract
We used dynamic force spectroscopy (DFS) to explore the energy landscape of interactions between a chelated uranyl compound and a monoclonal antibody raised against the uranyl-dicarboxy-phenanthroline complex. We estimated the potential energy barrier widths and the relevant thermodynamic rate constants along the dissociation coordinate. Using atomic force microscopy, four different experimental setups with or without the uranyl ion in the chelate ligand, we have distinguished specific and nonspecific binding in the binding affinity of the uranyl compound to the antibody. The force loading rates for our system were measured from 15 to 26,400 pN/s. The results showed two regimes in the plot of the most probable unbinding force versus the logarithm of the loading rate, revealing the presence of two (at least) activation barriers. Analyses of DFS suggest parallel multivalent binding present in either regime. We have also built a molecular model for the variable fragment of the antibody and used computational graphics to dock the chelated uranyl ion into the binding pocket. The structural analysis led us to hypothesize that the two regimes originate from two interaction modes: the first one corresponds to an energy barrier with a very narrow width of 0.5 +/- 0.2 A, inferring dissociation of the uranyl ion from its first coordination shell (Asp residue); the second one with a broader energy barrier width (3.9 +/- 0.3 A) infers the entire chelate compound dissociated from the antibody. Our study highlights the sensitivity of DFS experiments to dissect protein-metal compound interactions.
- Published
- 2007
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39. Canonical signal recognition particle components can be bypassed for posttranslational protein targeting in chloroplasts.
- Author
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Tzvetkova-Chevolleau T, Hutin C, Noël LD, Goforth R, Carde JP, Caffarri S, Sinning I, Groves M, Teulon JM, Hoffman NE, Henry R, Havaux M, and Nussaume L
- Subjects
- Arabidopsis ultrastructure, Chlorophyll metabolism, Chloroplast Proteins, Chloroplasts ultrastructure, Dimerization, Fluorescence, Genetic Complementation Test, Light-Harvesting Protein Complexes metabolism, Membrane Proteins metabolism, Models, Biological, Mutation genetics, Phenotype, Protein Binding, Protein Transport, Thylakoids metabolism, Arabidopsis metabolism, Arabidopsis Proteins metabolism, Chloroplasts metabolism, Signal Recognition Particle metabolism
- Abstract
The chloroplast signal recognition particle (cpSRP) and its receptor (cpFtsY) target proteins both cotranslationally and posttranslationally to the thylakoids. This dual function enables cpSRP to utilize its posttranslational activities for targeting a family of nucleus-encoded light-harvesting chlorophyll binding proteins (LHCPs), the most abundant membrane proteins in plants. Previous in vitro experiments indicated an absolute requirement for all cpSRP pathway soluble components. In agreement, a cpFtsY mutant in Arabidopsis thaliana exhibits a severe chlorotic phenotype resulting from a massive loss of LHCPs. Surprisingly, a double mutant, cpftsy cpsrp54, recovers to a great extent from the chlorotic cpftsy phenotype. This establishes that in plants, a new alternative pathway exists that can bypass cpSRP posttranslational targeting activities. Using a mutant form of cpSRP43 that is unable to assemble with cpSRP54, we complemented the cpSRP43-deficient mutant and found that this subunit is required for the alternative pathway. Along with the ability of cpSRP43 alone to bind the ALBINO3 translocase required for LHCP integration, our results indicate that cpSRP43 has developed features to function independently of cpSRP54/cpFtsY in targeting LHCPs to the thylakoid membranes.
- Published
- 2007
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40. NAD binding induces conformational changes in Rho ADP-ribosylating clostridium botulinum C3 exoenzyme.
- Author
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Ménétrey J, Flatau G, Stura EA, Charbonnier JB, Gas F, Teulon JM, Le Du MH, Boquet P, and Menez A
- Subjects
- ADP Ribose Transferases metabolism, Adenosine Diphosphate chemistry, Adenosine Diphosphate Ribose metabolism, Amino Acid Motifs, Binding Sites, Protein Conformation, ADP Ribose Transferases chemistry, Botulinum Toxins, NAD metabolism
- Abstract
We have solved the crystal structures of Clostridium botulinum C3 exoenzyme free and complexed to NAD in the same crystal form, at 2.7 and 1.95 A, respectively. The asymmetric unit contains four molecules, which, in the free form, share the same conformation. Upon NAD binding, C3 underwent various conformational changes, whose amplitudes were differentially limited in the four molecules of the crystal unit. A major rearrangement concerns the loop that contains the functionally important ARTT motif (ADP-ribosyltransferase toxin turn-turn). The ARTT loop undergoes an ample swinging motion to adopt a conformation that covers the nicotinamide moiety of NAD. In particular, Gln-212, which belongs to the ARTT motif, flips over from a solvent-exposed environment to a buried conformation in the NAD binding pocket. Mutational experiments showed that Gln-212 is neither involved in NAD binding nor in the NAD-glycohydrolase activity of C3, whereas it plays a critical role in the ADP-ribosyl transfer to the substrate Rho. We observed additional NAD-induced movements, including a crab-claw motion of a subdomain that closes the NAD binding pocket. The data emphasized a remarkable NAD-induced plasticity of the C3 binding pocket and suggest that the NAD-induced ARTT loop conformation may be favored by the C3-NAD complex to bind to the substrate Rho. Our structural observations, together with a number of mutational experiments suggest that the mechanisms of Rho ADP-ribosylation by C3-NAD may be more complex than initially anticipated.
- Published
- 2002
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41. Novel 3-(4-piperidinylthio)-1H-indoles as potent nonopioid orally active central analgesics.
- Author
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Potin D, Parnet V, Teulon JM, Camborde F, Caussade F, Meignen J, Provost D, and Cloarec A
- Subjects
- Administration, Oral, Analgesics, Non-Narcotic administration & dosage, Animals, Indoles administration & dosage, Mice, Analgesics, Non-Narcotic pharmacology, Indoles pharmacology
- Abstract
A series of 3-(4-piperidinylthio)-1H-indoles was synthesized and evaluated in mice in the phenylbenzoquinone(PBQ)-induced writhing and hot plate tests. Most of these compounds are good analgesics with activities comparable to that of morphine. Among them compound 1i (UP 237-61), which has a strong serotonin binding profile, has an interesting antinociceptive activity which is not reversed by naloxone.
- Published
- 2000
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42. Microtiter plate immunoenzymometric assay for estrogen receptor.
- Author
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Delage V, Teulon JM, Bellanger L, Seguin P, Descotes F, and Saez S
- Subjects
- Biopsy, Cytosol chemistry, Female, Humans, Sensitivity and Specificity, Adenocarcinoma chemistry, Breast Neoplasms chemistry, Immunoenzyme Techniques statistics & numerical data, Receptors, Estrogen analysis
- Abstract
The estrogen receptor (ER) status of breast cancer is used both as a prognostic factor and as a predictor of response to endocrine therapy. An immunoenzymometric assay for ER was developed on 96-well microtiter plates (EIA96). This technique involves two monoclonal antibodies directed against different epitopes in the B domain of ER. The two-step protocol (16-18 h and 3 h at 4 degrees C) requires 100 microL of cytosol. This assay showed a detection limit of 0.58 pmol/L. Intra- and interassay CVs of clinical specimens were < or = 5% except for the least concentrated sample (6.5 pmol/L, CV = 6.7%). In a comparison study involving cytosols of breast adenocarcinoma tissue biopsies, we compared the EIA96 with the radioligand assay (RLA) and the Abbott ER-EIA, widely used techniques for determining ER concentration in cytosols of breast cancer tumors. The two EIAs showed excellent agreement; however, two samples showed discrepant results by EIA96 and RLA.
- Published
- 1996
43. N6-substituted adenosine receptor agonists. Synthesis and pharmacological activity as potent antinociceptive agents.
- Author
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Güngör T, Malabre P, Teulon JM, Camborde F, Meignen J, Hertz F, Virone-Oddos A, Caussade F, and Cloarec A
- Subjects
- Adenosine antagonists & inhibitors, Adenosine chemical synthesis, Adenosine metabolism, Analgesia, Analgesics metabolism, Animals, Indoles antagonists & inhibitors, Indoles metabolism, Methylation, Mice, Molecular Structure, Nitrogen chemistry, Rats, Receptors, Purinergic P1 metabolism, Structure-Activity Relationship, Theophylline analogs & derivatives, Theophylline pharmacology, Adenosine analogs & derivatives, Analgesics chemical synthesis, Indoles chemical synthesis, Purinergic P1 Receptor Agonists
- Abstract
Novel N6-(indol-3-yl)alkyl derivatives of adenosine were synthesized. The adenosine receptor affinity and the antinociceptive activity of these compounds were assessed in binding studies and the phenylbenzoquinone-induced writhing test. Most of these analogues exhibited a potent analgesic activity without side effects. Among them, compound 3c (UP 202-32) bound to A1 (Ki = 110 nM) and A2 (Ki = 350 nM) adenosine receptors in a specific manner since it did not interact with many other receptors, especially opioid binding sites. The antinociceptive activity in the phenylbenzoquinone assay (ED50 = 3.3 mg/kg po) was antagonized by 8-cyclopentyltheophylline, suggesting that an adenosinergic mechanism underlies the analgesic activity observed with this compound. The data obtained with these new N6-substituted adenosine receptor agonists emphasize the interest of such compounds in the treatment of pain.
- Published
- 1994
- Full Text
- View/download PDF
44. Synthesis and angiotensin II receptor antagonist activity of C-linked pyrazole derivatives.
- Author
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Nicolaï E, Curé G, Goyard J, Kirchner M, Teulon JM, Versigny A, Cazes M, Virone-Oddos A, Caussade F, and Cloarec A
- Subjects
- Animals, Antihypertensive Agents pharmacology, Antihypertensive Agents therapeutic use, Biphenyl Compounds pharmacology, Biphenyl Compounds therapeutic use, Imidazoles pharmacology, Imidazoles therapeutic use, Losartan, Magnetic Resonance Spectroscopy, Pyrazoles chemical synthesis, Pyrazoles pharmacology, Pyrazoles therapeutic use, Rats, Tetrazoles chemistry, Tetrazoles pharmacology, Tetrazoles therapeutic use, Angiotensin Receptor Antagonists, Antihypertensive Agents chemical synthesis, Blood Pressure drug effects, Hypertension, Renal drug therapy, Pyrazoles chemistry
- Abstract
The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These 5-O-substituted and 5-C-substituted 3-alkylpyrazole derivatives represent a new series of antagonists and have led to the discovery of compounds with potent oral antihypertensive activity in a renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors. In vivo structure-activity relationship study has shown the importance of the 4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl moiety for oral activity and the critical role of alkyl substituents at the 1- or 2-position. In the case of oral administration, 5-C derivatives were found to be, on the whole, more potent than 5-O derivatives. UP 221-78, 5-hydroxymethyl-3-n-propyl-1-(2,2,2-trifluoroethyl)-4- [[2'-(1H-tetrazol-5-yl)biphenyl-4-]methyl]-1H-pyrazole (79), displayed equivalent antihypertensive activity to the well known antagonist Losartan at 3 mg/kg p.o. in renal artery-ligated rats, with maximal decreases in mean arterial pressure of 60 and 63 mmHg for Losartan and UP 221-78, respectively.
- Published
- 1994
- Full Text
- View/download PDF
45. Synthesis and SAR studies of novel triazolopyrimidine derivatives as potent, orally active angiotensin II receptor antagonists.
- Author
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Nicolaï E, Curé G, Goyard J, Kirchner M, Teulon JM, Versigny A, Cazes M, Caussade F, Virone-Oddos A, and Cloarec A
- Subjects
- Administration, Oral, Animals, Hypertension drug therapy, Male, Models, Molecular, Pyrimidines administration & dosage, Pyrimidines chemical synthesis, Pyrimidines therapeutic use, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Tetrazoles administration & dosage, Tetrazoles chemical synthesis, Angiotensin Receptor Antagonists, Azoles chemistry, Pyrimidines pharmacology, Tetrazoles pharmacology
- Abstract
The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These [1,2,4]-triazolo[1,5-c]pyrimidine and 1,2,4-triazolo[4,3-c]pyrimidine derivatives represent a new class of bicyclic antagonists that produced a potent, oral antihypertensive activity in the renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors and were found to be specific for the AT1 receptor subtype. A SAR study has shown the importance of the 8-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl for oral activity and the critical role of alkyl substituents at 5- and 7-positions. No significant differences were found between the [1,5-c] and [4,3-c]series. UP 269-6 (5-methyl-7-n-propyl-8-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl ]- [1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one, derivative 29) was selected as the lead compound. It was shown to be a highly potent antihypertensive derivative (decrease in mean arterial pressure of 39.6 +/- 7.2 mmHg at 1 mg/kg po in renal artery-ligated rat) with a long duration of action which displayed a high affinity for adrenal AII receptors with a marked selectivity for the AT1 receptor subtype (Ki AT1 = 24 nM; Ki AT2 = 79,200 nM). This compound is currently undergoing extensive pharmacological and clinical development.
- Published
- 1994
- Full Text
- View/download PDF
46. Synthesis and structure-activity relationships of novel benzimidazole and imidazo[4,5-b]pyridine acid derivatives as thromboxane A2 receptor antagonists.
- Author
-
Nicolaï E, Goyard J, Benchetrit T, Teulon JM, Caussade F, Virone A, Delchambre C, and Cloarec A
- Subjects
- Benzimidazoles pharmacology, Blood Platelets metabolism, Computer Simulation, Humans, Imidazoles chemistry, Imidazoles pharmacology, Models, Molecular, Molecular Structure, Purines pharmacology, Pyridines chemistry, Pyridines pharmacology, Radioligand Assay, Structure-Activity Relationship, Benzimidazoles chemical synthesis, Imidazoles chemical synthesis, Purines chemistry, Pyridines chemical synthesis, Receptors, Thromboxane antagonists & inhibitors
- Abstract
A series of 1-benzylbenzimidazole and 3-benzylimidazo[4,5-b]pyridine substituted in the 2-position by an alkanoic or mercaptoalkanoic acid chain was synthesized for evaluation as potential thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists. The affinity of each compound for washed human platelet TXA2/PGH2 receptors was determined by radioligand binding studies using [125I]PTA-OH. Structure-activity relationships led to the conclusions that 2-alkanoic acid derivatives were slightly more potent than 2-mercaptoalkanoic acids and that compounds possessing a 3,3-dimethylbutanoic acid in the 2-position were definitely the most potent with Ki values of 4-39 nM (11a, 11g-x, 37a, 37f-o, 23a-c). The replacement of this 3,3-dimethylbutanoic acid side chain by a shorter one led to a marked decrease of affinity (11b and 11c; Ki = 5600 and 1700 nM, respectively). Compounds of benzimidazole and imidazo[4,5-b]pyridine series displayed similar potencies (11q and 23c have Ki values of 6 and 7 nM, respectively). The interesting pharmacological profile of compound 23a (UP 116-77: 4-[3-[(4-chlorophenyl)methyl]-6-chloroimidazo[4,5-b]pyridin-2-yl]- 3,3-dimethylbutanoic acid) and its excellent tolerance led us to select this derivative for further development.
- Published
- 1993
- Full Text
- View/download PDF
47. Cardiotonic agents. Synthesis and cardiovascular properties of novel 2-arylbenzimidazoles and azabenzimidazoles.
- Author
-
Güngör T, Fouquet A, Teulon JM, Provost D, Cazes M, and Cloarec A
- Subjects
- Animals, Benzimidazoles chemistry, Benzimidazoles pharmacology, Cardiotonic Agents chemistry, Cardiotonic Agents pharmacology, Dogs, Female, Guinea Pigs, Heart Rate drug effects, Male, Models, Molecular, Myocardial Contraction drug effects, Rats, Structure-Activity Relationship, Benzimidazoles chemical synthesis, Cardiotonic Agents chemical synthesis
- Abstract
Novel 2-arylbenzimidazoles and azabenzimidazoles were synthesized, and their inotropic action was evaluated. Changes in left ventricular pressure, dP/dt max, were measured as an index of cardiac contractility. The structural features that impart optimal inotropic activity are presented. The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers. To investigate the mechanism of action, the most potent compounds were tested for their calcium-sensitizing properties and their potential for the inhibition of phosphodiesterase. Two compounds, 1 and 41, showed interesting in vitro and oral activity without side effects. They have a more potent calcium-sensitizing effect than MCI-154 and are under further investigation.
- Published
- 1992
- Full Text
- View/download PDF
48. Triterpenoid glycosides from the bark of Mimosa tenuiflora.
- Author
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Jiang YL, Massiot G, Lavaud C, Teulon JM, Guéchot C, Haag-Berrurier M, and Anton R
- Subjects
- Carbohydrate Sequence, Hydrolysis, Magnetic Resonance Spectroscopy, Methylation, Molecular Sequence Data, Saponins chemistry, Oleanolic Acid analogs & derivatives, Plants, Medicinal chemistry, Saponins isolation & purification
- Abstract
Two new saponins were isolated from Mimosa tenuiflora and their structures established as 3-O-[alpha-L-rhamnopyranosyl(1----2)-beta-D-glucopyranosyl-(1----3]-(alp ha-L- arabinopyranosyl-(1----4]-beta-D-xylopyranosyl-(1----2)]-[beta-D- xylopyranosyl-(1----4)]-beta-D-glucopyranosyl)-28-O-alpha-L-rhamnopyrano syl oleanolic acid and 3-O-[alpha-L-rhamnopyranosyl-(1----2)-beta-D-glucopyranosyl-(1----3]-(al pha- L-arabinopyranosyl-(1----4]beta-D-xylopyranosyl-(1----2)]-[beta-D- xylopyranosyl-(1----4)]-beta-D-glucopyranosyl) oleanolic acid.
- Published
- 1991
- Full Text
- View/download PDF
49. [p-[(Thienylcarbonyl)amino]phenoxy]propanolamines derivatives as diuretic and beta-adrenergic receptor blocking agents.
- Author
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Bouley E, Teulon JM, Cazes M, Cloarec A, and Deghenghi R
- Subjects
- Animals, Blood Pressure drug effects, Chemical Phenomena, Chemistry, Dogs, Female, Heart Rate drug effects, Male, Myocardial Contraction drug effects, Propanolamines chemical synthesis, Rats, Rats, Inbred Strains, Receptors, Adrenergic, beta drug effects, Structure-Activity Relationship, Diuresis drug effects, Propanolamines pharmacology, Receptors, Adrenergic, beta physiology
- Abstract
The synthesis of [[(thienylcarbonyl)amino]phenoxy]propanolamines and their beta-adrenergic blocking and diuretic activity are described. Structure-activity relationships demonstrated that ortho substitution of the phenoxy ring with an hydrogen or an ester function leads to compounds possessing both activities. Ethyl 2-[3-[(1,1-dimethylethyl) amino]-2-hydroxypropoxy]-5-[(2-thienylcarbonyl)amino]benzoate (3d) was selected as the most active compound for further investigation.
- Published
- 1986
- Full Text
- View/download PDF
50. Chemical structure of cibenzoline.
- Author
-
Teulon JM
- Subjects
- Chemical Phenomena, Chemistry, Anti-Arrhythmia Agents, Imidazoles
- Published
- 1987
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