23-Oct-2020 - Max-Planck-Institut für biophysikalische Chemie

World record resolution in cryo-electron microscopy

Novel technique visualizes individual atoms in a protein with cryo-electron microscopy for the first time

A crucial resolution barrier in cryo-electron microscopy has been broken. Holger Stark and his team at the Max Planck Institute (MPI) for Biophysical Chemistry have observed single atoms in a protein structure for the first time and taken the sharpest images ever with this method. Such unprecedented details are essential to understand how proteins perform their work in the living cell or cause diseases. The technique can in future also be used to develop active compounds for new drugs.

Since the outbreak of the COVID-19 pandemic, scientists around the world have been solving 3D structures of important key proteins of the novel coronavirus. Their common goal is to find docking sites for an active compound which can combat the pathogen effectively.

One method applied for that is cryo electron microscopy (cryo-EM), which can be used to make three-dimensional structures of biomolecules visible. As these are structurally highly flexible this is no easy task. To capture the fuzzy molecules without damaging them, they are cooled down extremely quickly, or shock-frozen so to speak. The frozen samples are thereafter bombarded with electrons, and the resulting images are recorded. Using these, the three-dimensional structure of the molecules can then be calculated. Three pioneers of this technique, Jacques Dubochet, Joachim Frank, and Richard Henderson, received the Nobel Prize in Chemistry for the development of cryo-EM in 2017.

World record for resolution allows to see individual atoms in proteins

Stark's group has now broken the cryo-EM resolution barrier with a unique cryo-electron microscope newly developed by this team. “We equipped our device with two additional electron-optical elements to further improve image quality and resolution. These ensure that imaging errors of optical lenses, so-called aberrations, no longer play a role,” explains the Max Planck director. His doctoral student Ka Man Yip adds: “Electron microscopes are optical instruments and physically resemble a camera. The aberrations of an electron microscope interfere in cryo-EM in much the same way as those of a camera in photography. For a much improved image quality it was therefore crucial to avoid these aberration errors.”

Using the new microscope, the scientists have taken more than one million images of the protein apoferritin to map the molecular structure with a resolution of 1.25 angstroms. One angstrom is equivalent to a ten millionth of a millimeter. “We now visualize single atoms in the protein – a milestone in our field,” explains structural biologist Stark. “For us, it was like putting super glasses on the microscope. The new structure reveals details never seen before: We can even see the density for hydrogen atoms and single atom chemical modifications.”

The great potential of cryo-EM for imaging of high-resolution 3D protein structures was also demonstrated by colleagues at the Medical Research Council Laboratory of Molecular Biology in Cambridge (UK). They achieved a similarly high resolution using a different approach. “It is now conceivable that cryo-EM will in future be able to achieve even subatomic resolutions,” says the Max Planck researcher.

Basis for structure-based drug design

But what is the benefit of being able to study a protein structure with such unprecedented atomic resolution? To understand how a man-made machine works, one has to observe its components directly at work. This is also true for proteins – the nanomachines of living cells. To get an idea how they carry out their tasks, one has to know the exact position of all atoms of the protein.

Such detailed insights are also relevant for structure-based drug design. Compounds for drugs are customized in a way that they bind to viral proteins, for example, and block their function. But what is the underlying mechanism of inhibition? Researchers can only elucidate and understand this if they can observe at atomic level how a compound and a viral protein interact. Such novel insights help to improve molecules for drugs and reduce side effects. “With breaking this cryo-EM resolution barrier, the technique has reached a level where the benefits for pharmaceutical developments are directly visible,” says Stark.

Max-Planck-Institut für biophysikalische Chemie

Recommend news PDF version / Print

Share on

Facts, background information, dossiers
  • cryo-electron microscopy
  • protein structure
  • proteins
More about MPI für biophysikalische Chemie
  • News

    Crystal structures in super slow motion

    Laser beams can be used to change the properties of materials in an extremely precise way. This principle is already widely used in technologies such as rewritable DVDs. However, the underlying processes generally take place at such unimaginably fast speeds and at such a small scale that th ... more

    Dissecting protein assemblies

    Super-resolution MINFLUX nanoscopy, developed by Nobel laureate Stefan Hell and his team, is able to discern fluorescent molecules that are only a few nanometers apart. In an initial application of this technique to cell biology, researchers led by Stefan Hell and Stefan Jakobs have now opt ... more

    Virus multiplication in 3D

    Vaccinia viruses serve as a vaccine against human smallpox and as the basis of new cancer therapies. Two studies now provide fascinating insights into their unusual propagation strategy at the atomic level. For viruses to multiply, they usually need the support of the cells they infect. In ... more

More about Max-Planck-Gesellschaft
  • News

    Clocking electron movements inside an atom

    Hard X-ray free-electron lasers (XFELs) have delivered intense, ultrashort X-ray pulses for over a decade. One of the most promising applications of XFELs is in biology, where researchers can capture images down to the atomic scale even before the radiation damage destroys the sample. In ph ... more

    A clear path to better insights into biomolecules

    An international team of scientists, led by Kartik Ayyer from the MPSD, has obtained some of the sharpest possible 3D images of gold nanoparticles. The resuts lay the foundation for obtaining high resolution images of macromolecules. The study was carried out at the European XFEL’s Single P ... more

    The Missing Step in the Water Warmup: First Bend and then Turn

    The water on Earth makes our planet inhabitable. It absorbs the Sun’s energy and releases it in the form of heat. An international research collaboration headed by the Max Planck Institute for Polymer Research (MPI-P) has now shown how and how fast the stored energy in the water molecules i ... more