Stephen Cusack
Head of EMBL Grenoble

EMBL Grenoble is a key player in the Partnership for Structural Biology (PSB) which integrates the activities of several Grenoble institutes involved with structural biology and thus is able to provide a uniquely comprehensive range of platforms for both inhouse research and external users.

A cornerstone of the PSB is the close interaction of EMBL Grenoble with European Synchrotron Radiation Facility (ESRF), which involves collaboration on building and operating beamlines for macromolecular crystallography and small-angle scattering, developing instrumentation and techniques, and providing expert help to visitors. The highly automated ESRF crystallography beamlines are equipped with EMBL-designed high-precision microdiffractometers and frozen crystal sample changers. A new X-ray small-angle scattering instrument built by ESRF and EMBL is now operational with a custom designed smallvolume automatic sample changer.

High throughput methods have also been introduced in other steps of the structure determination process. These include a very successful robotic system for nanovolume crystallisation and a novel high throughput screening method, ESPRIT, which enables soluble protein domains to be identified in otherwise badly expressed or insoluble proteins. More recently, a Eukaryotic Expression Facility (EEF) has been established specialising in the expression of multi-subunit complexes in insect cells, building on and further developing the MultiBac method. All these platforms are now available to external users under the EU funded BioStruct-X projects.

Overview on Research at EMBL Grenoble
With specialist research groups and teams in both scientific areas research at EMBL Grenoble outstation focuses on structural biology and molecular cell biology. In addition, a number of technology-focused instrumentation teams provide an invaluable resource of technical know how and support to aid the scientific community in the structural biology realm.
Structural Biology Research Groups Berger Group Structural complexomics of eukaryotic gene expression
Cusack Group Structural biology of RNA-protein complexes in gene expression and host-pathogen interactions
Hart Team High-throughput protein technologies
Marcia Group Structure and function of lncRNA-protein complexes involved in transcription regulation
Panne Group Structural biology of signal transduction and epigenetic gene regulation
Molecular Cell Biology Research Groups Pillai Group Regulation of gene expression by non-coding RNAs
Schaffitzel Team Ribosomal complexes: targeting, translocation and quality control
Structural Biology Technology and Instrumentation Teams Cipriani Team Diffraction Instrumentation Team
McCarthy Team Synchrotron Crystallography Team
Márquez Team High-throughput crystallisation laboratory
Neutron Diffraction Team Deuteration Isotope Labelling Facility

A strong tradition at the outstation is the study of systems involving protein-nucleic acid complexes and viruses. Structural work on aminoacyl-tRNA synthetases is particularly well known and has recently focussed on elucidation of the mode of action of novel boron-containing antibiotics, which target leucyl-tRNA synthetase. Projects involving protein-RNA interactions also include cryo-EM studies of the signal recognition particle and holo-translocon with the ribosome and other proteins and complexes involved in RNA processing, transport and degradation, such as the nonsense-mediated decay (NMD) pathway.

Other important areas include the analysis of mechanisms of transcriptional regulation, including at the epigenetic level: groups are working on the structural analysis of eukaryotic transcription factor and chromatin-modification complexes as well as elucidation of the mechanisms by which piRNAs (small non-coding RNAs) protect the genome. Another focus is the study of segmented RNA viruses, particularly influenza and bunyaviruses, with the aim of understanding how their polymerases replicate and transcribe the viral genome. Complementary to this are studies on the innate immune receptors which detect the presence viral RNA in infected cells and activate interferon production. The first crystal structures of domains of the influenza virus polymerase, determined in collaboration with other members of the CNRS-Grenoble University-EMBL Unit of Virus Host Cell Interactions (UVHCI) which is situated next to the outstation, have led to an important programme of anti-influenza drug design in collaboration with pharmaceutical companies.

Scientists at EMBL Grenoble have access to a wide range of techniques, including molecular biology and biophysical techniques, cryo-electron microscopy, isotope labelling, NMR, neutron scattering, X-ray crystallography and small angle scattering. A confocal microscope with facilities for cross-correlation spectroscopy is available for the study of complex formation in cells, as well as a top-end Polara electron microscope with direct detector and cryo-tomography capability.

Stephen Cusack
Head of EMBL Grenoble