Institut de Biologie StructuraleGrenoble / France


The prize Charles-Louis de Saulses de Freycinet awarded to Andrea Dessen

Every year, the french National Academy of Sciences awards prizes in different scientific areas. Among them, the price Charles-Louis de Freycinet is awarded for applications issued of molecular biology and dedicated to the prevention or cure of diseases.
In 2015 it was awarded to Andrea Dessen, research director at CNRS and head of the group "Bacterial Pathogenesis" at the IBS. The main goal of Andrea is the development of new antibiotherapies through structural and functional characterization of macromolecular complexes involved in the biosynthesis and repair of the bacterial wall. This award recognizes the importance of her results and the remarkable consistency of her research project.

Large Scale Conformational Dynamics Control the Function of H5N1 Influenza Polymerase

An international collaboration of scientists from the IBS (FDP group), the EMBL and the ILL has revealed the molecular function of a protein essential for replication of H5N1 influenza virus. Scientists used a combination of solution-state NMR, small-angle neutron scattering, small-angle X-ray scattering (SAXS), and Förster resonance energy transfer (FRET) to reveal structural changes in the 627-NLS domain of the Influenza A RNA polymerase. This domain is able to adopt two very different conformations, adjustable according to the needs of the virus. Depending on the temperature, this protein assumes a ‘close state’, allowing the polymerase to run and the viral proteins to be synthesized, or an ‘open-form’ observed here for the first time, giving its ability to interact with other proteins and thus allowing entry in infected cell nucleus. Switching from one conformation to another enables an essential part of the polymerase to enter the nucleus of the infected cell, where the viral genome is replicated. This study illustrates how the conformational flexibility of a protein allows it to adapt its function, facilitating infection of the host.

Press release

Large-Scale Conformational Dynamics Control H5N1 Influenza Polymerase PB2 Binding to Importin α. Delaforge E, Milles S, Bouvignies G, Bouvier D, Boivin S, Salvi N, Maurin D, Martel A, Round A, Lemke EA, Ringkjøbing Jensen M, Hart DJ, Blackledge M. Journal of the American Chemical Society;137(48):15122-34

Crystal structure of the global anaerobic transcriptional regulator FNR

Many anaerobic bacteria control pathogenic virulence and their defense against the immune system of their host, thanks to protein transcription regulators which contain FeS centers sensitive to oxygen. This is particularly true of bacteria causing gastroenteritis, urinary tract infections and anthrax. The Metalloproteins group of the IBS determined the first crystal structure of one of these controllers, the FNR (for Fumarate Nitrate Reduction regulator). This protein has been studied for over 20 years to understand how the action of oxygen affects the integrity of FeS centers and how this degradation regulates the binding of FNR to DNA, and thus the control of the gene expression. The work reported here will serve as a reliable source for new structural and functional studies aimed at further understanding the fascinating mechanism of O2-based regulation by FNRs and will help develop new antibiotic molecules targeted against this regulator.

The crystal structure of the global anaerobic transcriptional regulator FNR explains its extremely fine-tuned monomer-dimer equilibrium. A. Volbeda, C. Darnault, O. Renoux, Y. Nicolet, J.C. Fontecilla-Camps. Science Advances; Vol. 1, no. 11, e1501086

The Paoletti Prize awarded to Hugues Nury

Hugues Nury, research fellow at IBS (in the Membrane Tranporters group), will receive the prix Paoletti on Dec. 2 for his work on the structure of pentameric ligand-gated ion channels.

The Claude Paoletti Award is a scholarship from the Institute of Biological Sciences (CNRS), intended to support young researchers.

How do intrinsically disordered domains regulate specificity and activity of MAP kinases?

Mitogen-activated protein kinases are essential components of eukaryotic signal transduction networks that enable cells to respond appropriately to extracellular stimuli. The FDP group of the IBS, in collaboration with researchers at the EMBL-Grenoble, have succeeded in characterising the structure, dynamics, kinetics, affinity and stoichiometry of the signaling complex composed of the disordered domain of the MKK7 kinase and its cognate kinase JNK. The results from NMR and crystallography reveal that MKK7 can interact with JNK using two different binding modes that induce an “active” and an “inactive” state, respectively, of the JNK kinase. The results show how intrinsically disordered domains can regulate not only signaling specificity in the MAPK pathways, but also potentially the activity of cognate kinases.

Structure and dynamics of the MKK7-JNK signaling complex. Kragelj J, Palencia A, Nanao MH, Maurin D, Bouvignies G, Blackledge M, Jensen MR. Proc Natl Acad Sci U.S.A., 112, 3409-3414.

2015 Science Fair

In 2015, the national science festival, Fête de la Science, partnered with the International Year of Light. On this occasion, the IBS organized 4 events :

On October 05 & 06 at IBS, 66 secondary schools pupils and their 6 teachers explored the world of proteins at atomic scale. They discovered the experimental approaches in life science and scientific results obtained at the IBS as well as different careers in research:

Atelier microbiologie/ Microbiology workshop
Salle des spectromètres RMN/ NMR spectrometers room
Entrainement au maniement du pipetman/ Pipetman training course
Pêche aux cristaux de protéine

On October 08 & 09, with the help of IBS scientists,108 schoolchildren discovered the awesome world of biology:

Atelier protéines fluorescentes/Fluorescent proteins
Atelier ADN de bananes/Banana DNA
Atelier découverte des protéines/Proteins discovery

On October 10, PhD students set up an exhibtiion stand at the Mini Maker Fair ’Parvis des Sciences’ along with neighbouring institutes ILL, EMBL and ESRF. It demonstrates the complementarity of these institutes and the importance of geographical proximity

Visualisation de cristaux de protéine sous microscope/ Protein crystal investigation under microscope
Observation de structures 3D de proteine/ Have a look to 3D structure of proteins

The exhibition "La vie en lumière, lumière sur la vie" at Saint Martin d’Uriage (coordinated by Beate Bersch researcher at IBS) invites visitors to explore bioluminescent organisms and molecules.During the science festival, Beate welcomed 133 schoolpupils and 180 general public. The exhibition is open from september 25 to november 29:

About thirty five volunteers were mobilized for those events, thanks to make this event a success! .

New light on transit into and out of the nucleus of the cell

The essential mechanism by which molecules are transported into the nucleus of the cell has been revealed by an international collaboration implicating researchers at the Institut de Biologie Structurale (Grenoble), the EMBL (Heidelberg), the Heidelberg Insitute of Theoretical Studies, and the University of Cambridge. Combining in vitro and in vivo experimental observations and simulation, the consortium was able to demonstrate how nucleoporins, highly flexible proteins present in the pores of the nuclear envelope, create a selective barrier by exploiting multiple, weak interactions with the transporting proteins, allowing for rapid but selective passage into the nucleus. These results are published in Cell (8 October 2015) (to know more).

Plasticity of an ultrafast interaction between nucleoporins and nuclear transport receptors., Sigrid Milles et. al., Cell;163(3):734-45

Molecules can still move, even inside crystals

X-ray crystallography reveals the three-dimensional structure of a molecule, especially for therapeutic or biotechnological purposes. For the first time, a study has shown that residual movements continue to animate proteins inside a crystal and that this movement ’blurs’ the structures obtained via crystallography. The study stresses that the more these residual movements are restricted, the better the crystalline order. The results were published in Nature Communications on October 05, 2015 (more details)

Observing the overall rocking motion of a protein in a crystal. Peixiang Ma, Yi Xue, Nicolas Coquelle N, Jens D. Haller JD, Yuwen T, Ayala I, Mikhailovskii O, Willbold D, Colletier JP, Skrynnikov N R, Schanda P. Nature Communications; 6:8361

2015 Scientific Day

The IBS Scientific Day is held every year. The 8th edition took place on June 19, 2015 at the Centre technique du papier (Saint martin d’hères Campus). The scientific program included scientific presentations by half of the IBS groups, a poster session by all PhD students and post-docs and students in their second year of PhD introduced their poster by a short flash presentation. The poster price was awarded to Romain Berardozzi(DYNAMOP group).

Accueil par les bénévoles / Welcome by volunteers
Poster session

A lunch gathered 190 IBS members in a friendly spirit, suitable for the development of a vibrant and creative community.

A new approach and software to generalize serial protein crystallography at synchrotrons and XFELs

Interface graphique de NanoPeakCellThe advent of X-ray free electron lasers (XFELs) has driven the emergence of serial protein crystallography, whereby data are collected from myriads of randomly-oriented crystals at RT, rather than from a single crystal oscillated in the X-ray beam, at 100 K. Compellingly, the collection of serial data allows a more detailed and realistic description of structural protein dynamic and radiation damage at RT. Furthermore, it allows macromolecular structure determination from highly radiation sensitive micro- and/or nano-crystal, owing to the fact that each crystal is exposed only once. Alas, this data collection strategy is not largely widespread, especially in France, and this, for the following two reasons. Firstly, a large amount of crystalline sample is generally required to collect a full serial dataset, discouraging structural biologists working on difficult proteins. Secondly, know-how is lacking, notably in terms of data sorting and processing.
In the featured article, we reported on a new data collection strategy, based on the raster-scanning of a protein crystal slurry sandwiched between two solid supports, and which only requires 200-600 nl of settled crystals. We present the first version of our new pre-processing software, NanoPeakCell, able to sort, background-correct and Bragg-peak-search data produced by nearly all X-ray detectors used at synchrotrons (MARCCD, ADXV, PILATUS, EIGER, etc) and XFELs (MPCCD, CSPAD). The software and its graphical user interface are coded in Python, allowing painless installation and usage on various architectures (Linux, OS-X, etc). NanoPeakCell is currently being deployed at the ESRF, LCLS and SACLA, where it will hopefully allow users to more comprehensively sort, correct and process their serial data.

Raster-scanning serial protein crystallography using micro- and nano- focused synchrotron beams. Nicolas Coquelle, Aaron S. Brewster, Ulrike Kapp, Anastasya Shilova, Britta Weinhausen, Manfred Burghammer & Jacques-Philippe Colletier. Acta Crystallogr D; DOI :10.1107/S1399004715004514.

Near-atomic cryo-EM structure of the helical measles virus nucleocapsid

Measles is one of the most contagious human diseases. A first high resolution glimpse at how the measles virus genome is wrapped up in its protective nucleoprotein shell comes courtesy of cryo-electron microscopy. With the help of the state-of-the-art electron microscope of IBS, researchers of UVHCI and IBS in collaboration with EMBL
Heidelberg succeeded in solving the structure of the nucleoprotein-RNA helix at a world-beating resolution of 4.3 Å. This is the first near-atomic resolution three-dimensional cryo-electron microscopy reconstruction of a helical nucleocapsid of non segmented negative-strand RNA viruses, the viral order that includes many other
nefarious human pathogens like Rabies, Mumps and Ebola. The resulting atomic model of the Measles Virus nucleocapsid provides a platform for understanding viral replication and transcription and for specific antiviral drug design. This breakthrough has been published in Science.

Near-atomic cryo-EM structure of the helical measles virus nucleocapsid.Gutsche I, Desfosses A, Effantin G, Ling WL, Haupt M, Ruigrok RW, Sachse C, Schoehn G. Science;348(6235):704-7

Versatile Switch for Light-Controlled Cells

Scientists from IBS, Jülich, Frankfurt and Moscow uncovered the atomic structure of KR2, a light-driven transporter for sodium ions which had only recently been discovered. Based on the structural information the team then identified a simple way to turn KR2 from a sodium- into a potassium pump using simple means. Integrated into neurons, this could make KR2 a valuable tool for optogenetics, a new field of research that uses light-sensitive proteins as molecular switches to precisely control the activity of neurons and other electrically excitable cells using light impulses. The findings have been published in the journal Nature Structural and Molecular Biology (see the press release).

Crystal structure of a light-driven sodium pump. Ivan Gushchin, Vitaly Shevchenko, Vitaly Polovinkin, Kirill Kovalev, Alexey Alekseev, Ekaterina Round, Valentin Borshchevskiy, Taras Balandin, Alexander Popov, Thomas Gensch, Christoph Fahlke, Christian Bamann, Dieter Willbold, Georg Büldt, Ernst Bamberg & Valentin Gordeliy. Nature Structural & Molecular Biology; 22(5):390-5.

Direct observation of hierarchical protein dynamics

Proteins are complex machines that are in constant motion, moving continuously in order to carry out their functions. Their multiple component atoms also have their individual motion patterns, making the entire protein a system of non-stop highly complex movement. Understanding how a protein moves is the key to developing drugs that can efficiently interact with it. But because of its complexity, protein motion has been notoriously difficult to study. Scientists at IBS-Grenoble, EPFL and ENS-Lyon, have developed a new method for studying protein motion by first freezing proteins and then slowly “waking them up” with increasing temperature. The breakthrough method is published in Science.

Direct observation of hierarchical protein dynamics. Jozef Lewandowski, Maghan Halse, Martin Blackledge and Lyndon Emsley. Science;348(6234):578-81

Alzheimer’s disease markers could be identified through protein water mobility

A study of the water mobility on the surface of tau protein fibres has been conducted by a global team of scientists using neutron scattering experiments at the Institut Laue-Langevin (ILL) in Grenoble, France and the Jülich Centre for Neutron Science at the Heinz Maier-Leibnitz-Zentrum (MLZ) in Garching, Germany. The IBS scientists (from the Dynamics and kinetics of molecular processes Group) found water mobility on the surface of tau protein fibres is increased; the findings, reported in PNAS (Proceedings of the National Academy of Sciences of the United States of America), suggest that the movement of water molecules could be a marker for the presence of amyloid tau fibres and contribute to the detection of Alzheimer’s disease.

Press release

Hydration water mobility is enhanced around tau amyloid fibers. Y. Fichou, G. Schiro, F-X Gallat, C. Laguri, M. Moulin, J. Combet, M. Zamponi, M. Härtlein, C. Picart, E. Mossoud, H. Lortat-Jacob, J.P. Colletier, D. J. Tobiasi, M. Weik. PNAS;112(20):6365-70

Sugars against Henipavirus

Henipavirus (Hendra and Nipah) are class IV emerging viruses, causing highly lethal infections in Human and animals, and for which no treatment is currently available. In collaboration with Dr. Branka Horvat (International Center for Infectiology Research) and the P4-Jean Mérieux laboratory in Lyon, we have recently shown that these viruses used the interactive properties of complex polysaccharides termed Heparan Sulfate (HS), to bind to the surface of circulating leukocytes, thereby facilitating its dissemination in throughout the organism. We have also shown that heparin, a HS related polysaccharide, could inhibit this process and improved survival rates in a model of virus-infected golden hamsters. These results highlight the major role played by HS during Henipavirus infection and open new perspectives of antiviral treatments based on heparin derivatives..

Heparan sulfate-dependent enhancement of henipavirus infection. Mathieu C, Dhondt KP, Châlons M, Mély S, Raoul H, Negre D, Cosset FL, Gerlier D, Vivès RR, Horvat B. MBio; 6(2):e02427

Observing a “proteinquake” with an X-ray free electron laser

Protein structure is tailored to regulate and control chemical reactions essential for the biological function. Localized chemical events such as the breakage of a bond between a protein and a ligand may trigger a global protein conformational change. Using an X-ray free electron laser, an international team of researchers from the University of Rennes, the IBS, the University of Palermo, the LCLS (Stanford) and the KAIST (Korea) has tracked the motion of myoglobin in response to photoinduced ligand release, and observed a picosecond “proteinquake”. The results have just been published in Nature Communications.

Ultrafast myoglobin structural dynamics observed with an X-ray free-electron laser. Matteo Levantino*, Giorgio Schirò*, Henrik T. Lemke, Grazia Cottone, James M. Glownia, Diling Zhu, Mathieu Chollet, Hyotcherl Ihee, Antonio Cupane, and Marco Cammarata. Nature Communications 6: 6772.

How water molecules dance to activate proteins

An international team of researchers from the IBS (DYNAMOP group), the Institut Laue-Langevin, the Forschungszentrum Jülich, the University of California Irvine, the Australian Institute of Science and Technology Organisation, the Max Planck Institute Mülheim and the University of Perugia has shed light on the molecular mechanism behind the importance of water for functional protein dynamics. The scientists have discovered that water’s ability to flow on the surface of proteins makes them sufficiently dynamic to be biologically active. The results have just been published in Nature Communications on 03/16/2015.

Press release

Translational diffusion of hydration water correlates with functional motions in folded and intrinsically disordered proteins. Giorgio Schirò, Yann Fichou, François-Xavier Gallat, Kathleen Wood, Frank Gabel, Martine Moulin, Michael Hartlein, Matthias Heyden, Jacques-Philippe Colletier, Andrea Orecchini, Alessandro Paciaroni, Joachim Wuttke, Douglas Tobias, Martin Weik. Nature Communications;6:6490

Malene Ringkjøbing Jensen is the recipient of the CNRS bronze medal

Malene Ringkjøbing Jensen (IBS/FDP) is the recipient of a bronze medal of the CNRS 2015. This distinction rewards an on-going and fruitful research activity, which makes him/her a specialist with talent within a particular research field.

The research of Malene Jensen focuses on intrinsically disordered proteins, a class of proteins that remain functional despite the lack of a well-defined three-dimensional structure. Numerous intrinsically disordered proteins are associated with human diseases and Malene aims to elucidate the molecular mechanisms controlling the function of these proteins in order to potentially propose novel pharmacological solutions.
After obtaining her Ph.D. in 2006 at the Department of Chemistry, University of Copenhagen, she joined the group of Dr. Martin Blackledge (Protein Dynamics and Flexibility) at the Institut de Biologie Structurale (IBS) in Grenoble as a postdoctoral fellow. She was recruited by the CNRS in 2009 in order to continue her research activities at the IBS. Malene Jensen mainly uses nuclear magnetic resonance (NMR) spectroscopy in solution that provides information at atomic resolution about the structure and dynamics of proteins. In particular, NMR provides detailed insight into the conformational behaviour of disordered proteins and their interactions with physiological partners. Using experimental data from NMR in combination with computational methods, Malene Jensen has been able to contribute to the understanding of the role played by disordered proteins in the transcription and replication machinery of Measles virus as well as other members of the Paramyxoviridae family. Currently, her research focuses on understanding how intrinsically disordered proteins contribute to signalling specificity in the mitogen-activated protein kinase (MAPK) cell signalling pathways.

SAS models: how accurate are they?

The accuracy and uniqueness of models derived from small-angle scattering (SAS) data is a crucial topic in structural molecular biology. In a recent paper published in Acta D Cryst. Henry Kim and Frank Gabel (IBS/ELMA) discuss the influence of a hydration shell and restraints from NMR on the accuracy of SAS models.

Uniqueness of models from small-angle scattering data: the impact of a hydration shell and complementary NMR restraints.
H. S. Kim and F. Gabel (2015).
Acta Cryst. D71, 57-66.

Optical spectroscopies and X-ray crystallography: seeing the (in)visible

The Cryobench is a IBS/ESRF platform that allows users to perform various optical spectroscopy experiments (UV-visible light absorption, fluorescence, Raman) on crystals or several nanolitres of protein solution. This article describes the third version of the laboratory that has been installed on beamline ID29 of the ESRF. It also reviews more than 70 articles published since year 2000 featuring data recorded at the Cryobench. This should allow an inexperienced user to imagine what kind of experiment (s)he could carry out with his/her protein.

In crystallo optical spectroscopy (icOS) as a complementary tool on the macromolecular crystallography beamlines of the ESRF. von Stetten, D., Giraud, T., Carpentier, P., Sever, F., Terrien, M., Dobias, F., Juers, D. H., Flot, D., Mueller-Dieckmann, C., Leonard, G. A., de Sanctis, D. & Royant, A. Acta Cryst. D71, 15-26 (2015)

The strange behavior of super-cooled water under pressure

Super-cooled water submitted to high pressure undergoes several phase transitions, among others a first-order-like endothermic transition occurring at about 230 K that, in view of neutron scattering results, we were able to attribute to a liquid-liquid crossover.

Experimental evidence for a liquid-liquid crossover in deeply cooled confined water. Cupane A, Fomina M, Piazza I, Peters J, Schirò G. Physical Review Letters; 113(21):215701.

Visualizing the Molecular Recognition Trajectory of an Intrinsically Disordered Protein

For the first time, IBS researchers observed at atomic scale the trajectory and successive changes of shape of a viral disordered protein, from its free state to its attachment to another viral protein.The approach of this study, providing high-resolution structural and kinetic information about a complex folding and binding interaction trajectory, can be applied to a number of experimental systems to provide a general framework for understanding conformational disorder in biomolecular function and could lead to the development of innovative anti-viral.This study was published in Journal of the American Chemical Society 29 January 2015

Visualizing the Molecular Recognition Trajectory of an Intrinsically Disordered Protein Using Multinuclear Relaxation Dispersion NMR. Schneider R, Maurin D, Communie G, Kragelj J, Flemming Hansen D, Ruigrok R, Ringkjøbing Jensen M and Blackledge M. Journal of the American Chemical Society, 137 (3), 1220–1229

Winfried Weissenhorn, new director of the IBS

Winfried Weissenhorn took up his duty as sixth Director of the Institut de Biologie Structurale, on January 1rst, 2015, succeeding Eva Pebay Peyroula who spent 10 years at the head of the IBS

Winfried Weissenhorn received his PhD in Biochemistry in 1991 from the Ludwig Maximilians University in Munich. He performed his post doctoral training in structural biology at Harvard University and was Group leader in Structural Biology at EMBL Grenoble from 1998 to 2006. Since 2007 he is a full Professor in the Department of Chemistry and Biology at Grenoble University and he directed a research group at the international mixed Unit of Virus Host Cell Interactions (UVHCI) until December 2014 before moving to the IBS. He received the Line Renaud award from the FRM (Fondation pour la Recherche Médicale) in 2011 and he has been nominated senior member of the Institut Universitaire de France in 2012.
His main research areas are the structural biology of enveloped virus entry and budding. The Weissenhorn group aims to understand the conformational plasticity of the HIV-1 envelope glycoprotein notably its fusion protein subunit gp41, which mediates virus host cell entry. Because gp41 is also a target for broadly neutralizing antibodies structure-based immunogen development will be instrumental to define an Env based vaccine with broad efficacy. The second aim of the group is to understand the structural principles cellular complexes that are recruited by enveloped viruses including HIV-1 to facilitate virus release by membrane fission. The third aim of the group is the structural biology of innate immune factors that interfere with enveloped virus entry or budding.