Grenoble EPN campus: a unique place for structural biology research
The European Photon and Neutron (EPN) campus in Grenoble is a unique site hosting three international scientific research organisations – ILL, EMBL, ESRF – and a French research institute, the IBS. It is also a unique place for structural biology where researchers can find an unpaired set of beamlines, instruments and support facilities allowing for comprehensive investigations. Neutrons play a unique and highly complementary role. A review paper on the current and future perspectives for structural biology at the EPN campus has just appeared on the Journal of Synchrotron Radiation.
A feature article on the 50th Anniversary of the Stanford SSRL synchrotron radiation and protein crystallography, the paper provides details on the techniques and infrastructures currently available at the EPN campus in Grenoble. It also describes major contributions and future prospects.
It all started in 1967 with the foundation of the Institute Laue-Langevin (ILL). First neutrons were delivered in 1971. In 1975, the European Molecular Biology Laboratory (EMBL) established an outstation (now unit) adjacent to the ILL to study biological problems using neutrons, leading to many collaborations and important technical developments. The site underwent a major expansion with the establishment of the European Synchrotron Radiation Facility (ESRF) in 1988. To further leverage the scientific potential of the ESRF and ILL for structural biology, the CEA and the CNRS founded the IBS (Institut de Biologie Structurale) in 1992 (eventually moving to the EPN campus in 2013). In 2002, the Partnership for Structural Biology (PSB) was established, encompassing the EMBL, ESRF, IBS, ILL, with the aim of establishing a unique multi-disciplinary environment for integrated structural biology.
Today, thanks to continuous upgrade and modernisation programmes, the EPN campus offers fully state-of-the-art facilities. Through their Joint Structural Biology Group (JSBG) and beyond, the ESRF and the EMBL offer dedicated beamlines and instruments for structural biology studies, cryogenic electron microscopy and spectroscopy, and other support facilities.
The ILL supports biological neutron studies with dedicated laboratories for deuterium labelling (deuteration) of samples (D-Lab and L-Lab), two Small-Angle Neutron Scattering instruments (D11 and D22) dedicated to the analysis of the structure and function of complex biological systems (BioSANS) and two neutron crystallography instrument (DALI and LADI-III). Neutron scattering applications provide critical and unique insights into the structure and dynamics of biological systems at different time- and length-scales that are complementary to other techniques. Their unique advantages are maximised by the use of deuteration.
"The ability to produce customized deuterium-labelled biological molecules enables the optimization of neutron studies in solution scattering, crystallography, reflectometry and dynamics, significantly enhancing the scope, quality, and efficiency of research in these fields,” says Frank Gabel, head of the Biology, Deuteration, Chemistry and Soft matter Group at the ILL, who coordinates the support facilities, adding: “The ILL Deuteration (D) and Lipids (L) Labs have operated very successful user programs over the past decades and provided numerous tailor-made samples for a large number of successful neutron experiments, conducted both by collaborators from within the PSB network, as well as by international ILL user groups."
D11 and D22 are the primary small-angle neutron biological solution scattering (SANS) instruments at ILL. D22 offers an optimal flux-to-noise ratio and a combined SAXS/SANS setup, while D11 enables access to smaller Q-values In the words of Anne Martel, ILL scientists co-responsible of D22, "BioSANS has a particular place within the landscape of structural biology techniques: it provides unique information about macromolecular complexes in solution, and their conformational changes upon external stimuli. In complementarity with X-ray crystallography and Cryo-EM, its interpretation leads to a more comprehensive understanding of biological processes as they happen in vivo."
As for neutron crystallography, Matthew Blakeley. ILL scientist responsible for the intruments LADI-III and DALI, explains that it "complements synchrotron-based X-ray crystallography by accurately locating hydrogen and deuterium atoms in macromolecular structures at 1.5–2.5 Angstrom resolution. Moreover, the technique allows data collection from a single crystal at room- or cryo-temperatures without radiation damage. Identifying H/D positions provides crucial insights into protonation, hydrogen bonding and hydration, aiding enzymatic studies, ligand-binding analysis and structure-based drug design."
Structural biology deals with large molecules that play a crucial role in living organisms, such as proteins and nucleic acids. The structure of these macromolecules is intricately linked to their function, and structure changes thus affect their function. This kind of research is fundamental for example to undertand many diseases and to develop new diagnostic approches, vaccines or therapeutics.
Several techniques are used to look inside biological matter and unveal the structure and dynamics of molecules in complementary ways. These include X-rays and neutron scattering, as well as cryogenic electron microscopy (Cryo-EM) and spectroscopy. Experiments are complemented by models and computer simulations.
As for future developments, several challenges are clearly identified in the paper. Among them, the crucial role of probing the dynamic properties of macromolecules in order to understand how the function; and the power of multiscale and multimodal studies requiring the integration of the different cutting-edge technologies to address complex biological questions. Together, these innovations will consolidate the EPN campus as a hub for integrated structural biology, driving forward interdisciplinary research with transformative impacts on life sciences.
Reference:
A.A. McCarthy et al, 'Current and future perspectives for structural biology at the Grenoble EPN campus: a comprehensive overview', Journal of Synchrotron Radiation, Vol. 32, Part 3 (May 2025) https://doi.org/10.1107/S1600577525002012