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1 1 I H I G H L I G H T S 2 0 2 4

at beamline ID23-1 have revealed how transcription factor cooperativity shapes facial development, driving differences in facial appearance among individuals (page 20). These findings highlight how genetic regulation drives facial morphology and evolution. In the field of infectious diseases, MX at beamline ID29 has elucidated how metals promote enzyme oligomerization and enhance enzymatic activity, informing the design of inhibitors to combat antibiotic- resistant bacterial infections (page 22). Additionally, MX studies at beamlines ID23-1, ID23-2, ID29, and ID30A-1 have been instrumental in developing boron- based compounds targeting parasitic worm microbiota, offering promising treatments for debilitating parasitic infections (page 24). MX complementary techniques such as small-angle X-ray and neutron scattering (SAXS/SANS) have also advanced antimicrobial research. Combined SAXS at beamline BM29 and neutron scattering at the Institut Laue-Langevin (ILL) have revealed the structural stability of peptide assemblies forming nanostructures (page 26). Understanding these molecular characteristics provides a foundation for developing innovative biomedical applications, particularly next-generation antibiotics.

Notably, the integration of MX with AI offers now a powerful synergy, validating computational protein models and bridging the gap between theoretical predictions and experimental molecular behaviour. For instance, a study combining fully automated MX at beamline ID30A-1 and AI modelling has unveiled the sophisticated architecture of vertebrate egg coat filaments, providing new insights into fertility mechanisms (page 28). Beyond reproductive biology, this discovery sheds light on infertility disorders and paves the way for therapeutic advancements in reproductive medicine. In another breakthrough, researchers computationally designed water-soluble analogues of membrane proteins, which are critical drug targets that are often challenging to study due to their reliance on lipid environments for stability. High-resolution MX at beamlines ID23-1, ID29 and ID30B validated the structural integrity

and functional properties of these analogues, providing experimentally accessible alternatives that accelerate biomedical research and drug discovery (page 30).

Cryo-electron microscopy (cryo-EM) at the CM01 platform has delivered significant insights into neurological drug design. A study focused on vortioxetine, a multimodal antidepressant targeting serotonin receptors, revealed its species-specific mechanisms in humans and rodents (page 32). High-resolution cryo-EM structures showed that the human 5-HT3 serotonin receptor adopts an agonist- like conformation, while the mouse receptor remains in an inactive state. These findings provide a deeper understanding of ligand-receptor interactions and enable the development of targeted therapeutics for neurological disorders. Building on the successful operation of CM01 since 2017, a new cryo-EM facility (CM02), operated as a French Collaborative Research Group (CRG) beamline by the Institut de Biologie Structurale (IBS), was officially inaugurated last November and is already open to users.

Finally, SAXS at beamline BM29, combined with cryo-EM, unveiled the first natural molecular fractal: a microbial enzyme forming a Sierpiński triangle (page 34). This self- assembling fractal structure, previously observed primarily in synthetic systems, follows a mathematical pattern and demonstrates potential for indefinite growth. This ground- breaking discovery bridges molecular biology and fractal geometry, revealing the unexpected complexity of protein structures and their organization.

In conclusion, the studies highlighted in this chapter represent only a very small fraction of the science reported by our user community. Nevertheless, they emphasize the transformative impact of EBS across disciplines, offering insights into disease mechanisms, real-time cellular processes, and personalized medicine. •

M. SOLER LÓPEZ