Accueil > Research > Highlights > Archives > 2010
2010 ERC Starting Grant for Jerome Boisbouvier
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Biosynthesis of the bacterial cell wall
Bridging cell wall biosynthesis and bacterial morphogenesis. Matteï P-J, Neves D and Dessen A. Current Opinion in Structural Biology 20(6) : 749-755 ou 766 |
Some enzymes are the prisoners of a molecular cage !
Structure of RavA MoxR AAA+ protein reveals the design principles of a molecular cage modulating the inducible lysine decarboxylase activity. |
Structural biology : Proteins in dynamic equilibriumProtein molecules in solution exist as an equilibrium of different conformations. These different conformations and their proportions can not be studied by classical methods of structural biology. A report by the researchers from the Protein Dynamics and Flexibility by NMR Group shows how they can be measured in solution by NMR and small angle scattering. This article underlines the need to take into account the dynamics to better understand molecular biology. Structural biology : Proteins in dynamic equilibrium. Bernadó P, Blackledge M. Nature ;468(7327):1046-8. |
Relocation of Aurora B and survivin from centromeres to the central spindle impaired by a kinesin-specific MKLP-2 inhibitorThe chromosome passenger protein complex (CPC composed of Aurora B kinase, survivin, INCENP and borealin) is localized in the inner centromeres of sister chromatides during mitosis. The proteins of CPC are implicated in the spindle assembly checkpoint correcting the faulty attachments of spindle microtubules (MT) with the kinetochores. In anaphase, the loss of sister chromatide cohesion provokes the departure of the CPC from the centromeres to the spindle midzone MTs where the play an important role in cytodieresis. The migration of the CPC into the central spindle is dependent on the activity of a MT-based motor protein MKLP-2. Our paper describes the identification and characterization of the first specific inhibitor of MKLP-2. A library of 8 900 small molecules was screened for inhibition of the ATPase activity of MKLP-2 resulting to the identification of a small molecule inhibitor of MKLP-2, which we named paprotrain (PAssenger PROteins TRAnsport INhibitor). The inhibitor was uncompetitive with ATP and did not bind to the MT binding site of the MKLP-2 motor domain. Most importantly, the inhibitor was also able to target specifically MKLP-2 in cells by inhibiting the migration of CPC to the central spindle causing cytokinetic defects. The inhibitor will be a useful tool for chemical genetics to study the function of MKLP-2 in cytokinesis and to gain mechanistic insights, for example to exploit mechanistic differences between the various kinesins. Relocation of Aurora B and survivin from centromeres to the central spindle impaired by a kinesin-specific MKLP-2 inhibitor. Tcherniuk S, Skoufias DA, Labriere C, Rath O, Gueritte F, Guillou C, Kozielski F. Angew Chem Int Ed Engl. 2010 Oct 25 ;49(44):8228-31.
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More than the sum of its parts
Combining independent drug classes into superior, synergistically acting hybrid molecules. |
Unraveling K-turn RNA structure by a combination of NMR and small angle scattering
Structure of the K-turn U4 RNA : a combined NMR and SANS study. Falb, M., Amata, I., Gabel, F., Simon, B. and Carlomagno, T. Nucleic Acids Res. 38(18), 6274-6285. |
A new target for cancer drugs
Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2. |
Science Fair 2010In the framework of the 2010 French Science week, the IBS organized three events :
About fifty volunteers (almost 20% of IBS staff) were mobilized to welcome secondary school pupils and the lay public and helped to make it a successful event. |
A prize from the French Academy of Sciences awarded to Carlo Petosa (MMIP group leader)Each year, the French Academy of Sciences distributes about 80 prizes. The 2010 Montyon price was awarded to Carlo Petosa, MMIP group leader at the IBS. |
Artificial Metalloenzymes or tomorrow synthetic chemistryScientists from the CEA, the Université Joseph Fourier and the CNRS have recently developed a now approach combining protein crystallography and biomimetic chemistry to observe all the steps in oxygen activation, an essential reaction of life. In order to accomplish this, they have designed and crystallized an artificial metallo-enzyme consisting of a synthetic catalyst and a protein. The different states have been characterized by X-ray diffraction at the European Synchrotron Radiation Facility (ESRF). These results are an important step towards the design of artificial metallo-enzymes capable of synthetizing many industrially relevant molecules, both efficiently and at lower costs. This work, that opens new alternatives for a "green" chemistry approach has been published in the journal Nature Chemistry. Crystallographic snapshots of the reaction of aromatic C–H with O2 catalysed by a proteinbound iron complex. Christine Cavazza, Constance Bochot, Pierre Rousselot-Pailley, Philippe Carpentier, |
Bacterial cell wall observed by solid state NMRResearchers from the IBS, in collaboration with INAC, Newcastle University and the University of Liege, have characterized and compared the organization and dynamics of the cell wall of different bacterial species by solid state NMR. Rapid identification by NMR of molecular structures, in particular teichoïc acids, found on the surface of various strains and mutants, will help to identify genes and mechanisms involved in virulence. This work paves the way for studying the surface of other cell types and the observation of cell contacts during host/pathogen interactions. Dynamics characterization of fully hydrated bacterial cell walls by solid-state NMR : evidence for cooperative binding of metal ions. |
Light can repair what light has damagedUV-damage to DNA is potentially lethal to cells but can be handled by a dedicated enzyme, DNA photolyase which, most ingeniously, uses visible light for direct reversion of the most current lesions. The review discusses the reaction mechanisms of this flavoprotein. Reaction mechanisms of DNA photolyase. Brettel K and Byrdin M |
New potent and dual inhibitors of kinases involved in cancer cell proliferation and survivalThe casein kinase 2 (CK2) and Proviral Insertion Moloney virus kinases (Pim kinases) are serine/threonine kinases that have key roles in a wide variety cellular processes including cell differentiation, proliferation and survival. Very interestingly, they act on similar but not redundant pathways involved in tumorgenesis, making simultaneous inhibition relevant cancer therapy in particular for treatment of leukaemia, prostate cancer and lymphomas.
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Fifth scientific day and a new logo for IBSThe fifth IBS scientific day was held on June 28 on the Saint Martin d’Heres Campus. Nearly 150 members were present to listen to four plenary lectures and communications by four students belonging to one of the four research themes of the institute (program). A presentation was made of our actions for the Science Fair since 2004, as well as the workshops planned for the 2010 edition (details). In addition, participants could read twenty posters submitted by PhD students.
And last but not least, the IBS logo was presented :
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NatX-ray creates NatX-ray LLC in the USALaunched in April 2009, based on research carried on in Jean-Luc Ferrer’s team (IBS, Grenoble), NatX-ray SAS company just created NatX-ray LLC, a US subsidiary. This subsidiary is dedicated in a first time to the commercialization of consumables for crystallography. NatX-ray LLC is installed in San Diego, California, to take advantage of the proximity of famous research institutes involved in protein crystallography, such as the Salk Institute, the Scripps Institute, the Burnham Institute, La Jolla Institute for Allergy and Immunology as well as pharmaceutical companies (Novartis, Pfizer, ...) and biotech companies (Illumina, Active Sight, ...). This area offers already a significant market for NatX-ray products, and is the perfect starting point to reach the rest of the US market. |
Atomic description of HIV-1 protease enzyme in-actionThe three dimensional structure of a complex between active HIV-1 protease and a substrate oligopeptide, converted in-situ into a tetrahedral reaction intermediate(TI), has been determined using data to 1.76 Å resolution collected on the FIP-BM30A beamline at the ESRF. In this snapshot of the enzyme in-action, the TI and one of the two catalytic aspartates are engaged in a very short hydrogen bond, which gives an insight into enzyme mechanism. X-ray snapshot of HIV-1 protease in action : observation of tetrahedral intermediate and short ionic hydrogen bond SIHB with catalytic aspartate. Das A, Mahale S, Prashar V, Bihani S, Ferrer JL and Hosur MV. Journal of the American Chemical Society (2010) 132(18) : 6366-6373 |
Regulation of protease activity : when C1 inhibitor cooperates with heparinC1 inhibitor is a regulatory protein that controls the activity of several blood proteases involved in particular in innate immunity (complement system) and blood coagulation. Its reactive SERPIN (SERine Protease INhibitor) domain has been successfully produced in a recombinant form and characterized functionally using different methods, providing evidence that heparin potentiates its inhibitory activity towards proteases through an unusual « sandwich » mechanism. These data shed light on the mechanism of action of this inhibitor which plays a key role in the control of inflammation Functional characterization of the recombinant human C1 inhibitor serpin domain : insights into heparin binding. Rossi V, Bally I, Ancelet S, Xu Y, Frémeaux-Bacchi V, Vivès RR, Sadir R, Thielens N, Arlaud GJ. J Immunol, 184 : 4982-4989. |
Eva Pebay-Peyroula appointed Chairwoman of the National Research Agency (ANR)
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A new Isotope Labelling Approach for Direct Detection of CH/π Interactions in Protein
Direct detection of CH/pi interactions in proteins. Plevin MJ, Bryce DL, Boisbouvier J. Nat Chem. 2:466-71. Stereospecific isotopic labeling of methyl groups for NMR spectroscopic studies of high-molecular-weight proteins. Gans P, Hamelin O, Sounier R, Ayala I, Dura MA, Amero CD, Noirclerc-Savoye M, Franzetti B, Plevin MJ and Boisbouvier J. Angewandte Chemie International Edition, 49 : 1958-1962 |
The low temperature inflection in neutron scattering measurements of proteins is due to methyl rotationThe dynamic nature of protein structures is essential for macromolecular function and biological activity. Like in a motor operating The low temperature inflection in neutron scattering measurements of proteins is due to methyl rotation : direct evidence using isotope labelling and molecular dynamics simulations. |
Fight against HIV : a promising compound
Inhibition of DC-SIGN Mediated HIV infection by a linear trimannoside mimic in tetravalent presentation. Sattin S, Daghetti A, Thépaut M, Berzi A, Sanchez-Navarro M, Tabarani G, Rojo J, Fieschi F, Clerici M, Bernardi A. ACS Chem Biol. ;5(3):301-12. Interview RFI (in french only) |
A new labeling strategy to study complex biomolecules by NMR
Stereospecific Isotopic Labeling of Methyl Groups for NMR Spectroscopic Studies of High Molecular Weight Proteins. |
Hybrid Potential Simulations of Post-Transfer Editing in Aminoacyl-tRNA Synthetases
The Editing Mechanism of Aminoacyl-tRNA Synthetases Operates by a Hybrid Ribozyme/Protein Catalysis. Y. Hagiwara, O. Nureki, M. J. Field and M. Tateno. Journal of the American Chemical Society, 132(8):2751-8.. |
A new building for the Institut de Biologie StructuraleFrom its initial size of 100 people, the IBS has grown to an institute of over 220 individuals. It currently accomodates a start-up company and has plans to recruit young new international research teams. This steady growth made it necessary to envisage an expansion of the building and was accompanied by a desire for closer proximity to the other PSB institutes*. A first step was taken in 2006, when a request for funding was filed with the state/regional granting agency CPER. This was followed by a lengthy series of internal discussions, meetings with the three organizations that jointly operate the IBS (the CEA, the CNRS and the University Joseph Fourier), and negociations with the PSB partners and with local politicians. Thanks to strong support from the three operating organizations and from the director of the CEA-Grenoble, the end of 2009 saw two major hurdles overcome : land for a new building was acquired on the joint ESRF/ILL campus (recently renamed the “EPN campus”), and the funds needed to finance the project were secured. The new building, which was selected through competition, will have five floors and contain 8 000 m² of usable laboratory and office space. It will combine aesthetic architecture, a practical design intended to facilitate everyday research, and outstanding energy performance. After a period of detailed study, the request for a building permit will be submitted in July 2010, and work will begin in March 2011. The institute is scheduled to move into its new premises in spring 2013.
* Other PSB members include the European Synchrotron Radiation Facility (ESRF - one of the world’s most powerful sources of X-rays), the Institut Laue Langevin (ILL - the world’s leading neutron source), the European Laboratory of Molecular Biology (EMBL) |
Accessing the Unfolded part of the Proteome from NMR : A Step Forward in Structural BiologyThe central dogma that has motivated massive worldwide investment in structural genomic projects has been founded upon the assumption that the resolution of the three dimensional structure of a finite number of proteins will provide the key to understanding biological activity. However, over the last decade it has become increasingly clear that a large fraction (up to 40%) of the proteins encoded by the human genome are intrinsically disordered or contain disordered regions of significant length. These intrinsically disordered proteins (IDPs) are functional despite a lack of a stable structure. The classical structure-function paradigm therefore breaks down for this class of proteins, and new insight into the relationship between primary sequence and molecular function is required. The importance of developing new methodology to study these proteins is underlined by the fact that IDPs are associated with many human diseases, including cancer, cardiovascular disease, amyloidosis, neurodegenerative disease and diabetes. Vital molecular processes, their function, malfunction and potential inhibition by pharmaceutical agents, have escaped our attention for decades, and will continue to do so, unless we can develop the tools to study these elusive proteins. The development of meaningful descriptions of the conformational behavior of IDPs therefore represents a key challenge for contemporary structural biology. Recent advances at the Institut de Biologie Structurale (CEA-CNRS-UJF) in Grenoble using Nuclear Magnetic Resonance spectroscopy demonstrate that atomic resolution understanding of the behaviour of these proteins can be derived from the simplest NMR measurements, chemical shifts. Chemical shifts are uniquely dependent on local conformational sampling, and in this study it is shown that explicit consideration of the dynamic averaging of chemical shifts provides an accurate description of the ensemble of conformers present in solution. This breakthrough raises a long-standing, and fundamental barrier to our understanding of these intriguing proteins, and offers the very real prospect of following the conformational behavior of IDPs under conditions approaching those found in vivo, such as in crowded or even cellular environments. Defining Conformational Ensembles of Intrinsically Disordered and Partially Folded Proteins Directly from Chemical Shifts. M.R. Jensen, L. Salmon, G. Nodet and M. Blackledge. J Am Chem Soc, 132(4) : 1270-2 |
J. Boisbouvier and J. Joly received the CNRS Bronze medal and the CNRS CrystalOn Monday January 18, 2010, Jerome Boisbouvier (IBS/LRMN) received one of the CNRS’s 2008 Bronze Medals for its studying of macromolecular assemblies by NMR.
CNRS Crystals are given annually to a dozen engineers, technicians and administrative staff of the CNRS for their creativity and innovative contribution to research. |