Astrovirus structure: X-rayed star

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  • Published: Aug 1, 2011
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Astrovirus structure: X-rayed star

Viral revelations

X-ray crystallography reveals the structure of a common virus that causes gastroenteritis and juvenile diarrhoea, astrovirus, hinting at the development of potential drugs for this potentially lethal illness.

Rice University's Yizhi Jane Tao, postdoctoral researcher Jinhui Dong and their colleagues at National Autonomous University of Mexico have recently focused on the last of four small RNA viruses that can infect mammals and birds for which a crystal structure was not previously available. Astrovirus was first observed in detail using electron microscopy in 1975 and epidemiology pinpointed it as the cause of many outbreaks of diarrhoea in children, and sometimes adults. It turned out to be the second leading cause after rotavirus.

Human astrovirus, so-called because of its "star" shape, is transmitted orally via infected faecal matter. Although it is more of an inconvenience than a serious danger in well-nourished populations with access to clean water and healthcare, left untreated, children can become dehydrated. There is currently no vaccine or antiviral treatment against the pathogen, although good personal hygiene can reduce the risk of infection. In the developing world, it can be more problematic given the possibility of poor sanitation. All forms of diarrhoea are a significant problem and cause many childhood deaths through simple dehydration.


Symptomatic

Astrovirus causes symptoms once it reaches the lower part of the gastrointestinal tract. However, to reach its target after oral ingestion it must avoid protein-splitting enzymes, proteases, and the immune system. The researchers point out that astrovirus closely resembles hepatitis E virus (HEV) and Tao previously suggested that there might be a connection between the two. "Based on that assumption, we started to make constructs to see if we could produce, to start with, the surface spike on the viral capsid," she explains.

The astrovirus capsid is a hard 33-nanometre shell containing the viral RNA. It carries 30 protein spikes, each with a receptor-binding site that facilitates infection of the target intestinal cells in which viral replication takes place. However, such a simple statement belies the convoluted route to revealing the atomic-scale structure of the spike receptor.

Once the team had the atomic structure of the spike, finding the receptor site relied on additional investigative work to compare the genomic sequences of eight variants of astrovirus to find which were best conserved and so home in on the common receptor. In their search for this common receptor, the team discovered a shallow pocket in the spike that was the prime suspect for receptor binding.

"The size of the pockets suggests that it would most likely bind to sugar molecules, disaccharides or trisaccharides," Tao explains. "It may be that the virus binds to the sugar molecule and that helps it bind to the surface of a target cell."


Viral cousins

The team also showed that astrovirus resembles another of the four types of RNA-based viruses, calicivirus, which leads them to suspect that astrovirus may be a hybrid, with components derived from both HEV and calicivirus. The three viruses are certainly related but the researchers are yet to reveal the nature of this relationship genetically speaking. Nevertheless, the current understanding of the astrovirus structure might lead to the development of a new vaccine or an antiviral agent. A vaccine against HEV is currently in phase II clinical trials, so there is hope.

The team will now work with other research laboratories to identify compounds that can bind to the putative pocket, Tao adds. "We can do this computationally. We can screen 50,000 compounds, for example, to see which might bind to the protein with high affinity. Then we can start the optimization procedure," Tao says.



The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

 X-ray crystallography reveals the structure of a common virus that causes juvenile diarrhoea, astrovirus, hinting at the development of potential drugs for this often lethal illness.
Model of the astrovirus capsid

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