Abstract
Most life scientists would agree that understanding how cellular processes work requires structural knowledge about the macromolecules involved. For example, deciphering the double-helical nature of DNA revealed essential aspects of how genetic information is stored, copied and repaired. Yet, being reductionist in nature, structural biology requires the purification of large amounts of macromolecules, often trimmed off larger functional units. The advent of cryogenic electron microscopy (cryo-EM) greatly facilitated the study of large, functional complexes and generally of samples that are hard to express, purify and/or crystallize. Nevertheless, cryo-EM still requires purification and thus visualization outside of the natural context in which macromolecules operate and coexist. Conversely, cell biologists have been imaging cells using a number of fast-evolving techniques that keep expanding their spatial and temporal reach, but always far from the resolution at which chemistry can be understood. Thus, structural and cell biology provide complementary, yet unconnected visions of the inner workings of cells. Here we discuss how the interplay between cryo-EM and cryo-electron tomography, as a connecting bridge to visualize macromolecules in situ, holds great promise to create comprehensive structural depictions of macromolecules as they interact in complex mixtures or, ultimately, inside the cell itself.
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Acknowledgements
We are grateful to our group members and many colleagues for fruitful discussions. We thank those who provided figures for reproduction in this Review, and we apologize to those whose outstanding work we have not been able to cite due to the limited number of references. E.N. acknowledges support from the US National Institutes of Health (R35GM127018), the European Research Council (ERC-2022-SYG 101071583), and is a Howard Hughes Medical Institute Investigator. J.M. acknowledges valuable assistance from J. Dobbs, support from the EMBL, a European Research Council starting grant (3DCellPhase- 760067) and a Chan-Zuckerberg Initiative grant for Visual Proteomics.
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Nogales, E., Mahamid, J. Bridging structural and cell biology with cryo-electron microscopy. Nature 628, 47–56 (2024). https://doi.org/10.1038/s41586-024-07198-2
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DOI: https://doi.org/10.1038/s41586-024-07198-2
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