Viruses are miniature, highly efficient gene delivery machines. These infectious agents come in a wide variety of shapes and sizes, with most having a diameter between ten and a few hundred nanometers. Due to their size, analytical techniques such as electron microscopy provide valuable insights for diagnosis, treatment, and vaccine development.
Transmission electron microscopy, for example, is routinely used for fast virus detection and identification in diagnostic settings. Beyond viral diagnoses, electron microscopy is also on the forefront of virology, as it is used in virus structure and pathogenesis studies, especially though near-atomic resolution instruments like cryo-electron microscopes (cryo-EM).
Note the spike protein, visible as protrusions on the surface of each particle.
Image captured and pseudo-colored at the
NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.
The power of cryo-EM in virology
Imaging with cryo-electron microscopy does not necessitate typical negative staining or chemical fixation, as the sample is instead flash frozen in its native state. Cryo-EM features several techniques that can image virus structure, viral proteins, and virus-antibody immune complexes in 3D. Single particle analysis is a cryo-EM technique capable of determining high-resolution structures of macromolecular complexes such as the "spike" protein of coronaviruses. The cryo-EM technique known as cryo-electron tomography provides structural information with broader cellular context, such as viral assembly within bacteria.
Preparing for the next major virus
Viruses will doubtlessly continue to evolve and affect our world in devastating ways. Minimizing their impact will rely on the development of treatments and preventative measures driven by highly detailed insight into the nature and structure of viruses.
Cryo-EM has been used to study virus morphology for over 20 years, resolving the structure of viruses such as Zika, Ebola, HIV and coronaviruses. The near-atomic-resolution information provided by cryo-EM is critical for a better understanding of the molecular mechanisms behind antibody-antigen interactions. In fact, cryo-EM structures are increasingly used in protein epitope mapping, defining specific binding sites. These iterative studies aid the understanding of antibody mutations for faster discovery and development of more specific and effective vaccines or antiviral treatments.
Featured research
in the prefusion conformation, with the three subunits of the trimer
in red, green, and blue, and glycosylation in yellow.
Image created with PDB data (6VSB).
Battling the coronavirus at atomic scale with cryo-EM
As the global community fights against the COVID-19 pandemic, researchers have used electron microscopy, particularly cryo-EM, to increase our understanding of the SARS-CoV-2 virus. In January 2020, a Thermo Scientific 120kV TEM was first used to directly image the novel coronavirus in human cells at the National Institute for Viral Disease Control and Prevention (NIVDC), part of the China Centers for Disease Control in Beijing. In February, cryo-EM researchers determined the structure of the SARS-CoV-2 spike protein and its cellular receptor during infection using the Thermo Scientific Krios cryo-TEM. Researchers have made their cryo-EM structures publically available. By quickly solving the structure of the coronavirus spike protein, researchers used these results to develop a vaccine that entered phase 1 clinical trials in March 2020. Since then, more and more research groups around the world use cryo-EM to gain a detailed understanding of SARS-CoV-2 and to aid the development of vaccines, antivirals, and neutralizing antibodies.
Watch our webinar to learn more about the role of cryo-EM in coronavirus research ›
Below are some more examples of the successful application of cryo-EM in virology, highlighting the diversity of information that the technique can provide researchers.
The Zika virus, while initially transmitted by mosquito or tick, is infamous for passing from mother to unborn child, leaving the infant with a range of developmental and neurological defects. Researchers at Purdue University used cryo-EM to determine the structure of the entire virus particle with a 3.1 Å resolution; this is vital as viruses in this family appear otherwise identical at lower resolutions. These observations helped contribute to two potential vaccines currently in human trials.
Learn more about how cryo-EM is driving Zika virus research ›
Highly infectious and often fatal, outbreaks of the Ebola virus have imminently devastating consequences. Despite the danger it poses, there is still no effective treatment for this disease. Given the inherent danger of working with this virus, researchers are focused on studying viral components, which promise to accelerate the discovery of treatments and vaccines. For example, researchers at the Okinawa Institute of Science and Technology (OIST) determined the structure of the nucleocapsid-like assembly (which houses the genetic material of the virus) at near-atomic resolution. Understanding this component of the Ebola virus allows researchers to more accurately target the mechanism and spread of this deadly disease.
Learn more about how cryo-EM is impacting Ebola virus research ›
As a retrovirus, HIV introduces a copy of its genetic material into the DNA of the host, hijacking the machinery of the cell to produce further copies of itself. Research is focused on preventing the initial binding of the virus to the host cell and the integration of its genetic material into the host DNA. Researchers at Harvard Medical School employed cryo-EM to capture the structure of the fusion protein complex, which is believed to initiate the binding of the virus to the host cell. By fully understanding this structure, effective treatments that inhibit the binding mechanism can be produced.
Learn more about the impact cryo-EM has on HIV research by reading our blog ›
Prof. Jason McLellan answers questions about spike protein structure, cryo-EM and vaccine trials with collaborators at NIH. Filmed in March 2020, video courtesy of The University of Texas at Austin.
Cryo-electron microscopy (cryo-EM) is helping researchers determine the structure of coronavirus spike proteins—fueling strategies to prevent infections.
Structure-guided design of SARS-CoV-2 antivirals
Register to watch our recorded webinar from Dr. Quan Wang of ShanghaiTech University and Dr. Renhong Yan of Westlake University on new cryo-EM studies of the structural basis of key molecular processes including RNA replication/transcription and receptor recognition.
Cryo-EM for virology and vaccine design
Register to watch our recorded webinar from Dr. Jeff Lengyel, Thermo Fisher Scientific, on how cryo-electron microscopy has been used against viruses even the recent COVID-19 outbreak. Cryo-EM protein structure-based research has led to applications in virology and vaccine design.
Using cryo-EM for designing next-gen therapeutics against HIV
Register to watch our recorded webinar from Prof. Dmitry Lyumkis, Salk Institute for Biological Studies, on how HIV’s ability to integrate its genome into host DNA is vulnerable to inhibition and how cryo-EM studies for structure-based drug design can help combat global HIV epidemic.
Cryo-EM SARS-CoV-2 Selected Publications
SARS-CoV-2 structural protein and receptor studies
Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (2020). doi:10.1126/science.abb2507
Yan, R. et al. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science (2020). doi:10.1126/science.abb2762
Walls, A. C. et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell (2020). doi:10.1016/j.cell.2020.02.058
SARS-CoV-2 non-structural protein studies
Gao, Y. et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science (2020). doi:10.1126/science.abb7498
Yin, W. et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science (2020). doi:10.1126/science.abc1560
Hillen, H. S. et al. Structure of replicating SARS-CoV-2 polymerase. Nature (2020). doi:10.1038/s41586-020-2368-8
Wang, Q. et al. Structural basis for RNA replication by the SARS-CoV-2 polymerase. Cell (2020). doi:10.1016/j.cell.2020.05.034
SARS-CoV-2 neutralizing antibody studies
Cao, Y. et al. Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell (2020). doi:10.1016/j.cell.2020.05.025
Pinto, D. et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature (2020). doi:10.1038/s41586-020-2349-y
Prof. Jason McLellan answers questions about spike protein structure, cryo-EM and vaccine trials with collaborators at NIH. Filmed in March 2020, video courtesy of The University of Texas at Austin.
Cryo-electron microscopy (cryo-EM) is helping researchers determine the structure of coronavirus spike proteins—fueling strategies to prevent infections.
Structure-guided design of SARS-CoV-2 antivirals
Register to watch our recorded webinar from Dr. Quan Wang of ShanghaiTech University and Dr. Renhong Yan of Westlake University on new cryo-EM studies of the structural basis of key molecular processes including RNA replication/transcription and receptor recognition.
Cryo-EM for virology and vaccine design
Register to watch our recorded webinar from Dr. Jeff Lengyel, Thermo Fisher Scientific, on how cryo-electron microscopy has been used against viruses even the recent COVID-19 outbreak. Cryo-EM protein structure-based research has led to applications in virology and vaccine design.
Using cryo-EM for designing next-gen therapeutics against HIV
Register to watch our recorded webinar from Prof. Dmitry Lyumkis, Salk Institute for Biological Studies, on how HIV’s ability to integrate its genome into host DNA is vulnerable to inhibition and how cryo-EM studies for structure-based drug design can help combat global HIV epidemic.
Cryo-EM SARS-CoV-2 Selected Publications
SARS-CoV-2 structural protein and receptor studies
Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science (2020). doi:10.1126/science.abb2507
Yan, R. et al. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science (2020). doi:10.1126/science.abb2762
Walls, A. C. et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell (2020). doi:10.1016/j.cell.2020.02.058
SARS-CoV-2 non-structural protein studies
Gao, Y. et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science (2020). doi:10.1126/science.abb7498
Yin, W. et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science (2020). doi:10.1126/science.abc1560
Hillen, H. S. et al. Structure of replicating SARS-CoV-2 polymerase. Nature (2020). doi:10.1038/s41586-020-2368-8
Wang, Q. et al. Structural basis for RNA replication by the SARS-CoV-2 polymerase. Cell (2020). doi:10.1016/j.cell.2020.05.034
SARS-CoV-2 neutralizing antibody studies
Cao, Y. et al. Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell (2020). doi:10.1016/j.cell.2020.05.025
Pinto, D. et al. Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature (2020). doi:10.1038/s41586-020-2349-y
Drug Discovery
Learn how to take advantage of rational drug design for many more major drug target classes, leading to best-in-class drugs.
Infectious Disease Research
Cryo-EM techniques enable multiscale observations of 3D biological structures in their near-native states, informing faster, more efficient development of therapeutics.
Structural Biology Research
Cryo-electron microscopy enables the structural analysis of challenging biological targets such as large complexes, flexible species and membrane protein.
Pathology Research
Transmission electron microscopy (TEM) is used when the nature of the disease cannot be established via alternative methods. With nano-biological imaging, TEM provides accurate and reliable insight for certain pathologies.
Single Particle Analysis
Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.
Cryo-Tomography
Cryo-electron tomography (cryo-ET) delivers both structural information about individual proteins as well as their spatial arrangements within the cell. This makes it a truly unique technique and also explains why the method has such an enormous potential for cell biology. Cryo-ET can bridge the gap between light microscopy and near-atomic-resolution techniques like single-particle analysis.
Single Particle Analysis
Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.
Cryo-Tomography
Cryo-electron tomography (cryo-ET) delivers both structural information about individual proteins as well as their spatial arrangements within the cell. This makes it a truly unique technique and also explains why the method has such an enormous potential for cell biology. Cryo-ET can bridge the gap between light microscopy and near-atomic-resolution techniques like single-particle analysis.
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