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Structural biology: Publication in Nature Methods
A New Tool for Cryo-Electron Microscopy

Researchers at Jülich Research Center (Forschungszentrum Jülich – FZJ) and Heinrich Heine University Düsseldorf (HHU) headed by Professor Dr Carsten Sachse are making biomolecules visible at the atomic level using cryo-electron microscopy (cryo-EM for short). In an article published in the scientific journal Nature Methods, they present a new process that combines cryo-EM with a method otherwise used in materials research. The results have also been highlighted in a recent Nature Briefing.


Professor Dr Carsten Sachse next to the cryo-electron microscope of the Ernst Ruska-Centre for Microscopy and Spectroscopy with Electrons (ER-C) at Jülich Research Center (Forschungszentrum Jülich – FZJ). (Photo: FZJ / Sascha Kreklau)

The still relatively new technique of cryo-EM has a decisive advantage over X-ray crystallography that has been routinely in use for decades: Protein building blocks can be observed in their natural environment in a snap-frozen state without having to convert them into an artificial crystal beforehand. After snap-freezing, the transmission electron microscopy process is usually employed.

The alternative method that the researchers from Jülich and Düsseldorf have now employed, on the other hand, is a further development of scanning transmission electron microscopy with integrated differential phase contrast, or iDPC-STEM for short, which is used for snap-frozen samples.

“iDPC-STEM has so far been used primarily in materials research, where it has already led to very high resolutions. When imaging biological samples, we have now directly achieved a quality that was first made possible by cryo-electron microscopy a few years ago,” explains Carsten Sachse, Director of the Ernst Ruska-Centre at FZJ and Professor at HHU.

Together with research partners from the analytics company Thermo Fischer Scientific in Eindhoven, Netherlands, he was able to map protein structures using iDPC-STEM with a sub-nanometre resolution of 3.5 angstroms (Å) – one angstrom corresponds to 10-10 m.

“Cryo-electron microscopy is a bit more advanced today in comparison. But our results show that iDPC-STEM is in principle capable, with some optimisation, of achieving similar resolutions to today’s cryo-EM and expanding the possibilities for structural analysis; especially for very heterogeneous, non-uniform samples or single particles when averaging capabilities are limited,” says Professor Sachse.

In conventional cryo-electron microscopy, thousands, sometimes tens or hundreds of thousands, of snapshots of a sample are taken from many viewing directions. A powerful computer uses these images to calculate a detailed three-dimensional model of the molecule or particle.

Scanning electron microscopy, on the other hand, scans objects line by line in tiny steps to produce a composite image that includes just as many biomolecules and, as in conventional cryo-EM, serves as the basis for the three-dimensional structure calculation. As with cryo-electron microscopy, a low-dose electron beam is used because biomolecules are typically extremely sensitive. This prevents the high energy of the beam from destroying the sensitive structures.

Original publication

Ivan Lazić, Maarten Wirix, Max Leo Leidl, Felix de Haas, Daniel Mann, Maximilian Beckers, Evgeniya V. Pechnikova, Knut Müller-Caspary, Ricardo Egoavil, Eric G.T. Bosch, Carsten Sachse, Single-particle cryo-EM structures from iDPC-STEM at near-atomic resolution, Nature Methods (2022), 5 September 2022

DOI: 10.1038/s41592-022-01586-0

Nature Briefing

Kategorie/n: Schlagzeilen, Auch in Englisch, Math.-Nat.-Fak.-Aktuell, Forschung News, Forschungsnews Englisch

Microscopic image (top) and structure (bottom) of the tobacco mosaic virus (left) and protein hemocyanin (right) by iDPC-STEM. The 3D structures at the bottom are shown at 3.5 and 6.5 Å resolution. (Images: Ivan Lazić and Carsten Sachse)


Artistic rendering of the scanning transmission electron microscopy (STEM) approach: A small electron beam rasters over the sample in small steps to illuminate the snap-frozen biomolecules in ice. (Image: Daniel Mann and Carsten Sachse)

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