Towards integrated multimodal structural biology

“Structural biology has advanced dramatically in the last two decades and we now have a panoply of techniques available that can provide us with unprecedented insights into molecular structures and functions”, explains Montse Soler López, head of the structural biology group at the ESRF.

To date, more than 18 000 structures deposited in the Protein Data Bank and 16000 publications have stemmed from experiments carried out at the ESRF and the Institut Laue Langevin, in the EPN science campus. This is testimony of the successful Partnership for Structural Biology (PSB) with the ESRF, ILL, the European Molecular Biology Laboratory Grenoble outstation (EMBL) and the Institut de Biologie Structurale (IBS).

Today high-throughput cryogenic and room-temperature macromolecular crystallography (MX) enables scientists to determine the precise 3D structures of proteins, crucial for understanding diseases and designing targeted drugs. Time-resolved serial synchrotron crystallography (TR-SSX) goes a step further, capturing molecular movements at ultrafast timescales, shedding light on dynamic processes like enzyme function or drug binding.

Beyond crystallography, small-angle X-ray and neutron scattering (SAXS/SANS) allow researchers to study biomolecules in their natural, flexible states, providing a more realistic view of how they interact in biological systems.

A major leap forward comes from cryo-electron microscopy (cryo-EM) which can visualize molecular machines in near-native conditions, without the need for crystallisation. Building on this, cryo-electron tomography (cryo-ET) enables the visualisation of the internal architecture of cells, organelles, and protein complexes in situ. X-ray tomography, meanwhile, provides a broader view of global cellular organization, revealing how organelles are arranged, how viruses enter cells, and how structural changes unfold across cell populations. Together, they bridge the gap between molecular and cellular scales, offering a truly multiscale perspective on how molecules assemble into complex biological structures.

“We are continuously enhancing and upgrading our beamlines and instruments to redefine what’s possible in structural biology research”, says Soler López. This includes integrating  artificial intelligence-driven workflows and data processing, which enable rapidly analysing vast datasets and improving the accuracy of structural models.

“We’ve come a long way in structural biology, from the Nobel-awarded structure determination of cellular ion channel receptors to the ground-breaking advances in computational protein design”, explains Michael Krisch, director of research for Life Sciences. “With eight beamlines at the ESRF, four neutron instruments at the ILL, two cryo-EM facilities, and multiple specialized labs, we offer an uniquely integrated platform to study molecular structures from multiple, complementary angles” he concludes.

Reference:

McCarthy, A. A. et al, Journal of Synchrotron Radiation, Volume 32| Part 3| May 2025|

https://doi.org/10.1107/S1600577525002012

Text by Montserrat Capellas Espuny

Top image: A view of ID30B at the ESRF. Credits: S. Candé.