Angelovski G.,Max Planck Institute for Biological Cybernetics |
Toth E.,CNRS Center for Molecular Biophysics
Chemical Society Reviews | Year: 2017
A great deal of research involving multidisciplinary approaches is currently dedicated to the understanding of brain function. The complexity of physiological processes that underlie neural activity is the greatest hurdle to faster advances. Among imaging techniques, MRI has great potential to enable mapping of neural events with excellent specificity, spatiotemporal resolution and unlimited tissue penetration depth. To this end, molecular imaging approaches using neurotransmitter-sensitive MRI agents have appeared recently to study neuronal activity, along with the first successful in vivo MRI studies. Here, we review the pioneering steps in the development of molecular MRI methods that could allow functional imaging of the brain by sensing the neurotransmitter activity directly. We provide a brief overview of other imaging and analytical methods to detect neurotransmitter activity, and describe the approaches to sense neurotransmitters by means of molecular MRI agents. Based on these initial steps, further progress in probe chemistry and the emergence of innovative imaging methods to directly monitor neurotransmitters can be envisaged. © 2017 The Royal Society of Chemistry.
Bunzli J.-C.G.,Korea University |
Bunzli J.-C.G.,Ecole Polytechnique Federale de Lausanne |
Eliseeva S.V.,CNRS Center for Molecular Biophysics |
Eliseeva S.V.,Institute for Advanced Studies
Chemical Science | Year: 2013
The enthralling properties of lanthanide luminescence have propelled luminescent probes, tags and materials based on these elements to the forefront of science and technology. In this minireview, attention is focused on the latest innovations and on less-known aspects of this field. Exciting new developments in bioimaging, therapy, drug delivery, security tags, luminescent sensors, and solar energy conversion are highlighted. © 2013 The Royal Society of Chemistry.
Calligari P.A.,Ecole Normale Superieure de Paris |
Kneller G.R.,CNRS Center for Molecular Biophysics |
Kneller G.R.,Synchrotron Soleil
Acta Crystallographica Section D: Biological Crystallography | Year: 2012
A new application of the ScrewFit algorithm [Kneller & Calligari (2006), Acta Cryst. D62, 302-311] is presented which adds the detection of protein secondary-structure elements to their detailed geometrical description in terms of a curve with intrinsic torsion. The extension is based on confidence and persistence criteria for the ScrewFit parameters which are established by analyzing the structural fluctuations of standard motifs in the SCOP fold classes. The agreement with the widely used DSSP method is comparable with the general consensus among other methods in the literature. This combination of secondary-structure detection and analysis is illustrated for the enzyme adenylate kinase.© 2012 International Union of Crystallography Printed in Singapore - all rights reserved.
Boiteux S.,CNRS Center for Molecular Biophysics |
Jinks-Robertson S.,Duke University
Genetics | Year: 2013
DNA repair mechanisms are critical for maintaining the integrity of genomic DNA, and their loss is associated with cancer predisposition syndromes. Studies in Saccharomyces cerevisiae have played a central role in elucidating the highly conserved mechanisms that promote eukaryotic genome stability. This review will focus on repair mechanisms that involve excision of a single strand from duplex DNA with the intact, complementary strand serving as a template to fill the resulting gap. These mechanisms are of two general types: those that remove damage from DNA and those that repair errors made during DNA synthesis. The major DNA-damage repair pathways are base excision repair and nucleotide excision repair, which, in the most simple terms, are distinguished by the extent of single-strand DNA removed together with the lesion. Mistakes made by DNA polymerases are corrected by the mismatch repair pathway, which also corrects mismatches generated when single strands of non-identical duplexes are exchanged during homologous recombination. In addition to the true repair pathways, the postreplication repair pathway allows lesions or structural aberrations that block replicative DNA polymerases to be tolerated. There are two bypass mechanisms: an error-free mechanism that involves a switch to an undamaged template for synthesis past the lesion and an error-prone mechanism that utilizes specialized translesion synthesis DNA polymerases to directly synthesize DNA across the lesion. A high level of functional redundancy exists among the pathways that deal with lesions, which minimizes the detrimental effects of endogenous and exogenous DNA damage. © 2013 by the Genetics Society of America.
Fiorini F.,French Institute of Health and Medical Research |
Boudvillain M.,CNRS Center for Molecular Biophysics |
Hir H.L.,French Institute of Health and Medical Research
Nucleic Acids Research | Year: 2013
The RNA helicase Upf1 is a multifaceted eukaryotic enzyme involved in DNA replication, telomere metabolism and several mRNA degradation pathways. Upf1 plays a central role in nonsense-mediated mRNA decay (NMD), a surveillance process in which it links premature translation termination to mRNA degradation with its conserved partners Upf2 and Upf3. In human, both the ATP-dependent RNA helicase activity and the phosphorylation of Upf1 are essential for NMD. Upf1 activation occurs when Upf2 binds its N-terminal domain, switching the enzyme to the active form. Here, we uncovered that the C-terminal domain of Upf1, conserved in higher eukaryotes and containing several essential phosphorylation sites, also inhibits the flanking helicase domain. With different biochemical approaches we show that this domain, named SQ, directly interacts with the helicase domain to impede ATP hydrolysis and RNA unwinding. The phosphorylation sites in the distal half of the SQ domain are not directly involved in this inhibition. Therefore, in the absence of multiple binding partners, Upf1 is securely maintained in an inactive state by two intramolecular inhibition mechanisms. This study underlines the tight and intricate regulation pathways required to activate multifunctional RNA helicases like Upf1. © The Author(s) 2012. Published by Oxford University Press.
Hinsen K.,CNRS Center for Molecular Biophysics |
Hinsen K.,Synchrotron Soleil
Journal of Chemical Information and Modeling | Year: 2014
The MOlecular SimulAtion Interchange Conventions (MOSAIC) consist of a data model for molecular simulations and of concrete implementations of this data model in the form of file formats. MOSAIC is designed as a modular set of specifications, of which the initial version covers molecular structure and configurations. A reference implementation in the Python language facilitates the development of simulation software based on MOSAIC. © 2013 American Chemical Society.
Morfin J.-F.,CNRS Center for Molecular Biophysics |
Toth E.,CNRS Center for Molecular Biophysics
Inorganic Chemistry | Year: 2011
Gallium complexes are gaining increasing importance in biomedical imaging thanks to the practical advantages of the 68Ga isotope in Positron Emission Tomography (PET) applications. 68Ga has a short half-time (t 1/2 = 68 min); thus the 68Ga complexes have to be prepared in a limited time frame. The acceleration of the formation reaction of gallium complexes with macrocyclic ligands for application in PET imaging represents a significant coordination chemistry challenge. Here we report a detailed kinetic study of the formation reaction of the highly stable Ga(NOTA) from the weak citrate complex (H 3NOTA = 1,4,7-triazacyclononane-1,4, 7- triacetic acid). The transmetalation has been studied using 71Ga NMR over a large pH range (pH = 2.01-6.00). The formation of Ga(NOTA) is a two-step process. First, a monoprotonated intermediate containing coordinated citrate, GaHNOTA(citrate), forms in a rapid equilibrium step. The rate-determining step of the reaction is the deprotonation and slow rearrangement of the intermediate accompanied by the citrate release. The observed reaction rate shows an unusual pH dependency with a minimum at pH 5.17. In contrast to the typical formation reactions of poly(amino carboxylate) complexes, the Ga(NOTA) formation from the weak citrate complex becomes considerably faster with increasing proton concentration below pH 5.17. We explain this unexpected tendency by the role of protons in the decomposition of the GaHNOTA(citrate)* intermediate which proceeds via the protonation of the coordinated citrate ion and its subsequent decoordination to yield the final product Ga(NOTA). The stability constant of this intermediate, log K GaHNOTA(citrate) = 15.6, is remarkably high compared to the corresponding values reported for the formation of macrocyclic lanthanide(III)-poly(amino carboxylates). These kinetic data do not only give mechanistic insight into the formation reaction of Ga(NOTA), but might also contribute to establish optimal experimental conditions for the rapid preparation of Ga(NOTA)-based radiopharmaceuticals for PET applications. © 2011 American Chemical Society.
Divita G.,CNRS Center for Molecular Biophysics
Chemistry and Biology | Year: 2010
Jones et al. (2010) propose an innovative strategy for the development of bioactive cell-penetrating peptides. They combine computer-based design with specific targeting to elaborate a potent cell-penetrating bioactive peptide derived from cytochrome C. This short chimera peptide induces tumor cell apoptosis by targeting and sequestering nucleoporin, a key component of the nuclear pore complex. © 2010 Elsevier Ltd.
Pichon C.,CNRS Center for Molecular Biophysics |
Billiet L.,CNRS Center for Molecular Biophysics |
Midoux P.,CNRS Center for Molecular Biophysics
Current Opinion in Biotechnology | Year: 2010
Chemical vectors for non-viral gene delivery are based on engineered DNA nanoparticles produced with various range of macromolecules suitable to mimic some viral functions required for gene transfer. Many efforts have been undertaken these past years to identify cellular barriers that have to be passed for this issue. Here, we summarize the current status of knowledge on the uptake mechanism of DNA nanoparticles made with polymers and liposomes, their endosomal escape, cytosolic diffusion, and nuclear import of pDNA. Studies reported these past years regarding pDNA nanoparticles endocytosis indicated that there is no clear evident relationship between the ways of entry and the transfection efficiency. By contrast, the sequestration of pDNA in intracellular vesicles and the low number of pDNA close to the nuclear envelop are identified as the major intracellular barriers. So, intensive investigations to increase the cytosolic delivery of pDNA and its migration toward nuclear pores make sense to bring the transfection efficiency closer to that of viruses. © 2010 Elsevier Ltd.
Piazza F.,CNRS Center for Molecular Biophysics
Physical Biology | Year: 2014
In this paper we propose a novel theoretical framework for interpreting long-range dynamical correlations unveiled in proteins through NMR measurements. The theoretical rationale relies on the hypothesis that correlated motions in proteins may be reconstructed as large-scale, collective modes sustained by long-lived nonlinear vibrations known as discrete breathers (DB) localized at key, hot-spot sites. DBs are spatially localized modes, whose nonlinear nature hinders resonant coupling with the normal modes, thus conferring them long lifetimes as compared to normal modes. DBs have been predicted to exist in proteins, localized at few hot-spot residues typically within the stiffest portions of the structure. We compute DB modes analytically in the framework of the nonlinear network model, showing that the displacement patterns of many DBs localized at key sites match to a remarkable extent the experimentally uncovered correlation blueprint. The computed dispersion relations prove that it is physically possible for some of these DBs to be excited out of thermal fluctuations at room temperature. Based on our calculations, we speculate that transient energy redistribution among the vibrational modes in a protein might favor the emergence of DB-like bursts of long-lived energy at hot-spot sites with lifetimes in the ns range, able to sustain critical, function-encoding correlated motions. More generally, our calculations provide a novel quantitative tool to predict fold-spanning dynamical pathways of correlated residues that may be central to allosteric cross-talk in proteins. © 2014 IOP Publishing Ltd.