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.

Facts, background information, dossiers
More about MPI für biophysikalische Chemie
  • News

    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

    How the coronavirus multiplies its genetic material

    When someone becomes infected with the novel coronavirus SARS-CoV-2, the pathogen proliferates rapidly in the cells of the infected person. To do so, the virus has to multiply its genetic material, which consists of a single long RNA strand. This task is performed by the viral “copy machine ... more

    Predicting slippery spots for the ribosome

    In the genetic blueprint for proteins, the information for each amino acid is encoded by codons. A codon consists of three consecutive building blocks of messenger RNA (mRNA), a base triplet that encodes exactly one amino acid. During protein synthesis, adaptor molecules - called tRNAs - sp ... more

More about Max-Planck-Gesellschaft
  • News

    Cellular powerplant recycles waste gases

    Carbon monoxide is a very poisonous gas. Humans die within minutes when they inhale it. However, some microorganisms tolerate carbon monoxide and even use it to breathe and replicate. Knowledge about how these bacteria survive opens a window into the primeval times of the earth and the orig ... more

    "Cool" Bacteria

    Because of mild winters, ski resorts produce artificial snow to supplement the natural snowfall or extend the ski-season. Ice-nucleating proteins, extracted from the bacterium Pseudomonas syringae, can make ice better than any other known material and are already used in snow making. Resear ... more

    COVID-19: Calculating aerosol infection risk yourself

    An easy-to-use algorithm can now be used to determine the risk of being infected by SARS-CoV-2 via aerosol particles from patients in indoor environments. It also estimates how protective measures such as wearing masks and ventilation reduce the risk. The model, developed by researchers at ... more

  • Videos

    Epigenetics - packaging artists in the cell

    Methyl attachments to histone proteins determine the degree of packing of the DNA molecule. They thereby determine whether a gene can be read or not. In this way, environment can influence the traits of an organism over generations. more

    Biomaterials - patent solutions from nature

    Animals and plants can produce amazing materials such as spider webs, wood or bone using only a few raw materials available. How do they achieve this? And what can engineers learn from them? more

    Chaperones - folding helpers in the cell

    Nothing works without the correct form: For most proteins, there are millions of ways in which these molecules, composed of long chains of amino acids, can be folded - but only one way is the right one. Researchers in the department "Cellular Biochemistry" at the Max Planck Institute for Bi ... more

  • Research Institutes

    Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V.

    The research institutes of the Max Planck Society perform basic research in the interest of the general public in the natural sciences, life sciences, social sciences, and the humanities. In particular, the Max Planck Society takes up new and innovative research areas that German universiti ... more