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Structural-biology method crosses a key resolution threshold. A founding principle of structural biology is that, once researchers can directly observe macromolecules in enough detail, it should be possible to understand how their 3D structures confer their biological functions. Indeed, many scientific advances have relied on directly observing the world around us in as much detail as possible, and efforts are increasingly being dedicated to visualizing the atomic structures of biological components that have a key role in human disease. Nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography and cryo-electron microscopy (cryo-EM) are the three main structural-biology techniques in use. Of the three, cryo-EM has emerged as the current ‘go to’ method for determining the structures of large and dynamic complexes that have proved difficult to obtain by the other approaches. Writing in Nature, Yip et al.1 and Nakane et al.2 report the sharpest images yet obtained by using a method termed single-particle cryo-EM, enabling the location of individual atoms in a protein to be determined for the first time. Breakthroughs reported by other groups have also produced notable improvements in the resolution of cryo-EM images3,4. Ultimately, these developments will help researchers gain a better understanding, at unprecedented resolution, of how proteins work in health and disease, with the potential to aid the design of better therapeutics. Although cryo-EM is a decades-old technique, it has garnered increasing interest since around 2013 due to a series of technological and algorithmic advances that together drove a striking improvement in the resolution obtainable by this technique (described as the ‘resolution revolution’)
Collecting single-particle cryo-EM data begins with a protein sample that has been applied to a special sample grid. Plunging it into liquid ethane flash-freezes and traps the protein particles in a thin film of amorphous ice. Two-dimensional images of the individual particles in the sample grid, obtained by applying a beam of electrons, are averaged computationally to yield a 3D structure. The 2D images are incredibly ‘noisy’ because a low dose of electrons must be used to avoid damaging the radiation-sensitive biological sample. As such, these images have historically been unsuitable for determining structures at an atomic level of detail. However, the advances reported since 2013 have allowed single-particle cryo-EM data to be collected that rival those obtained using X-ray crystallography. The resolution revolution of cryo-EM has continued to advance6. Yip et al. and Nakane et al. harnessed technological improvements to determine the structures of a stable iron-storing protein called ferritin (termed apoferritin in the absence of metals) to a resolution of approximately 1.2 ångströms. These structures are the highest-resolution single-particle cryo-EM reconstructions so far determined, and the data are of sufficiently high quality to resolve the individual atoms in apoferritin (Fig. 1). This unprecedented feat would not have been thought feasible merely a decade ago....
