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Cryo–electron microscopy reveals the atomic details of apoferritin, a hollow, spherically shaped protein complex that stores iron.

Paul Emsley/MRC Laboratory of Molecular Biology

Cryo–electron microscopy breaks the atomic resolution barrier at last

If you want to map the tiniest parts of a protein, you only have a few options: You can coax millions of individual protein molecules to align into crystals and analyze them using x-ray crystallography. Or you can flash-freeze copies of the protein and bombard them with electrons, a lower resolution method called cryo–electron microscopy (cryo-EM). Now, for the first time, scientists have sharpened cryo-EM’s resolution to the atomic level, allowing them to pinpoint the positions of individual atoms in a variety of proteins at a resolution that rivals x-ray crystallography’s.

“This is just amazing,” says Melanie Ohi, a cryo-EM expert at the University of Michigan, Ann Arbor. “To see this level of detail, it’s just beautiful.” Because the heightened resolution reveals exactly how complex cellular machines carry out their jobs, improvements in cryo-EM should yield countless new insights into biology.

To map protein structures, scientists have been using x-ray crystallography since the late 1950s. By bombarding crystallized proteins with x-rays and analyzing the way the x-rays ricochet off, scientists can work out a protein’s likely makeup and shape. Decades of improvements to the x-ray beams, detectors, and computer power have made the approach fast and accurate. But the approach doesn’t work well when proteins are exceptionally large, work in complexes such as the ribosome, or can’t be crystallized, as is the case with many proteins that sit in cell membranes. 

In contrast, researchers using cryo-EM fire electrons at copies of frozen proteins that need not be crystallized; detectors record the electrons’ deflections, and sophisticated software stitches the images together to work out the proteins’ makeup and shape. Researchers in Japan had previously shown they could narrow the resolution to 1.54 angstroms—not quite reaching the point where they could distinguish individual atoms—in a gut protein called apoferritin, which binds and stores iron. Now, with the help of improvements in electron beam technology, detectors, and software, two groups of researchers—from the United Kingdom and Germany—have narrowed that to 1.25 angstroms or better, sharp enough to work out the position of individual atoms, they report today in Nature.

The enhanced resolution could accelerate a shift to cryo-EM already underway among structural biologists. For now, the technique only works with proteins that are unusually rigid. Next, researchers will strive to achieve similar sharp resolution with less rigid, large protein complexes, such as the spliceosome, a large complex of proteins and RNA molecules that cuts out “introns” from RNA destined to be converted into proteins.