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Single particle analysis taking biological research to the next level

Recent advances in technology have led to great developments in many fields – especially the field of medicine. In particular, better image detection has vastly improved electron microscopes, allowing for closer study of macromolecular complexes. The ability to visualize macromolecules in more detail, however, has raised even more questions to explore in the field of microscopy. To help us elucidate some of these questions, we turned to Professor Yoshinori Fujiyoshi, the Editor-in-Chief of the journal Microscopy. We spoke with Prof. Fujiyoshi about the journal’s latest special issue, “Single-Particle Cryo-Electron Microscopy,” to learn about the important role of this imaging method in current scientific research.

What, exactly, is single-particle cryo-electron microscopy?

Cryo-electron microscopy provides projection images of molecules and/or molecular complexes that are suspended and randomly oriented in a buffer layer. These images are classified according to the projection image type and averaged in each group with the same orientation in the buffer layer. Successful averaging of these single-particle images can dramatically improve the signal-to-noise ratio over that of the original images. The larger number of images could fundamentally provide a better signal-to-noise ratio, as well as better resolution of the averaged images. The three-dimensional structure at a high-resolution is then reconstructed from these averaged images.

What is the impact of single-particle analysis on current scientific research?

Before advancing this method, high-resolution structures were analyzed based only on crystallography. Crystallization, however, is generally very difficult or even impossible. Single-particle cryo-electron microscopy enables us to analyze high-resolution structures without first producing crystals of those structures. This method has dramatically changed the field of structural biology. Actually, more and more researchers, not only structural biologists, but also those in wider research fields of biology, have become interested in applying this method to their research.

Prof. Fujiyoshi
Professor Yoshinori Fujiyoshi. Image provided by the author. Used with permission.

Why is this important for society as a whole?

High-resolution structures of biological macromolecules are very important for understanding biological functions at the molecular level, as atomic models of biomolecules enable us to elucidate the function of the molecule in detail. After 2000, pharmaceutical companies initiated “evidence-based drug development”, and have more recently begun to apply the concept of “structure-guided drug development”. Effective structural analyses are required not only to enhance our understanding of basic biology, but also for applied sciences such as drug development. As mentioned before, single-particle analysis allows us to study high-resolution structures without crystallization and in a relatively short period of time. Pharmaceutical companies are therefore very interested in this method.

What do you think are the challenges being faced in single-particle cryo-electron microscopy research?

To respond to this question, I would like to provide you with an example. The most important drug target is thought to be G-protein coupled receptors (GPCRs) and researchers in basic biology and pharmaceutical companies anticipate that the single-particle method will soon elucidate the structures of GPCRs. The molecular weights of GPCRs are currently too small for this method, however, and thus structural analysis of GPCRs is a current challenge facing single-particle cryo-electron microscopy. Technological improvements of this method could help to elucidate the structures of GPCRs.

Why did you select this topic for this year’s Microscopy special issue?

As I mentioned before, many researchers, not only in structural biology, but also in much wider research fields, are interested in single-particle cryo-electron microscopy. The advancing curves of knowledge about this method and also results analyzed by this method have been dramatic and I think this year is perfect timing for the special issue of Microscopy.

What did you enjoy most about working on this special issue?

Guest Editors Yifan Cheng and Thomas Walz have been my good friends for many years and I enjoyed exchanging mail with them regarding this special issue. I was also very happy to see that these Guest Editors selected the very best researchers in this field of single-particle analysis, and I enjoyed learning from these researchers’ outstanding reviews.

Featured image credit: Examples of membrane protein structures determined by single-particle cryo-EM. Density maps are shown as gold surfaces and atomic models as red ribbon diagrams. The black lines indicate the approximate position of the membrane. © The Author 2015. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. Used with permission.

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