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Combatting COVID-19 with crystallography and cryo-EM


Crystallography and cryo-electron microscopy are vital tools in the fight against COVID-19, allowing researchers to reveal the molecular structures and functions of the SARS-CoV-2 virus, paving the way for new drugs and vaccines. Since the start of the pandemic, the ESRF has mobilised its crystallography and cryo-electron microscopy expertise and made its new Extremely Brilliant Source available as part of the collective effort to address this critical global health challenge.

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When the WHO declared the outbreak of COVID-19 a public health emergency of international concern in early 2020, it signalled the start of a race against time for scientists to understand how the newly identified SARS-CoV-2 virus functioned and to develop treatments for the disease. Structural biologists around the world pitched in, determining the structures of most of the 28 proteins encoded by the novel coronavirus. This remarkable collective effort resulted in over a thousand 3D structural models of SARS-CoV-1 and SARS-CoV-2 proteins deposited in the Protein Data Bank (PDB) public archive in just one year [1]. Researchers and drug developers rely on these models to design antiviral drugs, therapies and vaccines. However, the speed and urgency with which the SARS-CoV-2 protein structures were solved means that errors could inevitably slip in, with potentially severe consequences for drug designers targeting certain parts of the virus’s structure. 

Enter the Coronavirus Structural Task Force, an international team of 25 structural biologists offering their time and expertise to fix errors in structural models of the virus’s proteins in order to give drug designers the best possible templates to work from. Gianluca Santoni, crystallography data scientist in the ESRF’s structural biology group, is part of the task force, whose work is detailed in an article recently published in Nature Structural & Molecular Biology [2]. “Every week, we check the PDB for any new protein structure related to SARS-CoV-2,” he explains. “We push structural biology tools and methods to the limit to get every last bit of information from the data, to evaluate the quality and improve the models where possible.” 


Gianluca Santoni, pictured here at beamline ID23-1, brings his expertise in protein crystallography data collection and analysis to the Coronavirus Structural Task Force. Santoni developed the serial synchrotron crystallography data analysis software ccCluster at the ESRF and is interested in the optimisation of data collection strategies and the automation of data processing in macromolecular crystallography. Photo: ESRF/S. Candé.

The team encourages and supports scientists to update their entries in the PDB as well as making the improved structures available freely and publicly for other scientists, modellers and drug developers around the world [3]. The reaction from such communities has been extremely positive. “We realised that around 95% of the users who downloaded the structures weren’t structural biologists, and may have been unaware of the errors,” explains Santoni. “So for us, it was a way to contribute to the collective effort against COVID-19, applying our tools and developments to a real-life case.” 

Another key avenue of COVID-19 research is into monoclonal antibodies – synthetic proteins that behave like human antibodies in the immune system. Virus-neutralising antibodies can be used to treat symptomatic patients but also to protect other groups, such as individuals who respond poorly to vaccines. A team of researchers from the UK and EMBL Grenoble, have used the ESRF macromolecular crystallography beamline ID30A-1 to identify highly potent virus-neutralising antibodies from hundreds of anti-SARS-CoV-2 antibodies deep-sequenced from acute COVID-19 patients. To understand how the virus is inhibited and neutralised at a molecular level, the crystal structures of ACE-2 (the entry point for the SARS-CoV-2 virus) blocking and non-blocking antibodies were determined at the ESRF to 2.35 and 2.80 Å resolution, respectively. The results yield important insights into early antibody response and could help pave the way towards developing new anti-SARS-CoV-2 monoclonal antibody treatments [4]. 



The coronavirus research project ‘COVNSP3’ is based on the use of the ESRF’s cryo-electron microscope facility, led by Eaazhisai Kandiah (pictured). Photo: ESRF/S. Cande.

The ESRF’s cryo-electron microscopy (cryo-EM) beamline, CM01, is also mobilised for coronavirus research. As part of a research project selected by the French Agence Nationale de Recherche (ANR) [5], a team of scientists from the ESRF and the Institut de Biologie Structurale (IBS) on the EPN Science Campus are using a combination of molecular biology methods and sophisticated cryo-EM approaches to study the structure of an important therapeutic target, the novel coronavirus’s non-structural polyprotein 3, or Nsp3. "If we can reveal the atomic structure of Nsp3, this might point to possible new binding sites for potential drugs that could stop the virus making the proteins that it needs to reproduce," explains Eaazhisai Kandiah, project leader and beamline scientist at CM01.

"These innovative research projects show that the ESRF’s structural biology expertise – in both X-ray crystallography and cryo-electron microscopy – is an important weapon in the armoury in the collective fight against COVID-19," said Gordon Leonard, acting director of research for life sciences at the ESRF.

[2] T.I. Croll et al., Nat. Struct. Mol. Biol. (2021);
[4] G. Buller et al., biorxiv (2021);

Text: Anya Joly

Top image: Kristopher Nolte / Coronavirus Structural Task Force