Rice University scientists have defined the structure -- down to the atomic level -- of a virus that causes juvenile diarrhea. The research may help direct efforts to develop medications that block the virus before it becomes infectious.
The new paper by Professor Yizhi Jane Tao, postdoctoral researcher Jinhui Dong and their colleagues was published in today's online edition of the Proceedings of the National Academy of Sciences.
Tao's Rice lab specializes in gleaning fine details of viral structures through X-ray crystallography and computer analysis of the complex molecules, ultimately pinpointing the location of every atom. That helps researchers see microscopic features on a virus, like the spot that allows it to bind to a cell or sites that are recognized by neutralization antibodies.
Among four small RNA viruses that typically infect people and animals, Tao said, astrovirus was the only one whose atomic structure was not yet known. First visualized through electron microscopy in 1975, it became clear in subsequent studies that the virus played a role in juvenile -- and sometimes adult -- outbreaks of diarrhea, as the second leading cause after rotavirus. Passed orally, most often through fecal matter, the illness is more inconvenient than dangerous, but if left untreated, children can become dehydrated.
The virus works its foul magic in humans' lower intestines, but to get there it has to run a gauntlet through the digestive tract and avoid proteases, part of the human immune system whose job is to destroy it. (Though one, trypsin, actually plays a role in activating astrovirus, she said.) When the astrovirus finds a target and viral RNA is let loose inside human cells, virus replication starts. If the host's immune system does not do a good enough job in removing the viruses, the malady will run its uncomfortable course in a couple of days.Astrovirus bears a strong resemblance to the virus that causes hepatitis E (HEV). Tao, an associate professor of biochemistry and cell biology, said she decided to investigate astrovirus after completing a similar study of HEV two years ago. "I was thinking there's some connection between those viruses," she said. "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."
Once the atomic structure of the spike was known, finding the receptor site took detective work that involved comparing genomic sequences of eight variants of astrovirus to find which were the best conserved. "Among those eight serotypes, we figured there must be a common receptor, and that should be conserved on the surface," said Dong, the paper's lead author.
In looking for the common receptor, the team found a shallow pocket in the spike that became a prime suspect for receptor binding.
The researchers also discovered the astrovirus may have a sweet tooth. "The size of the pockets suggests that it would most likely bind to sugar molecules, like disaccharides or trisaccharides," Tao said. "It may be that the virus binds to the sugar molecule and that helps it bind to the surface of a target cell."
Finally, the team also determined astrovirus resembles another of the four types of RNA-based viruses, calicivirus, although more remotely than HEV. They suspect astrovirus may be a hybrid, with parts derived from both HEV and calicivirus. "Clearly, these three are related somehow. It's an interesting point, but we can't determine that relationship based on what we know right now."
What researchers can do is begin to develop a vaccine or antiviral drug that will block astrovirus. "There's already a phase II vaccine (in trials) for HEV, so that gives us hope," Dong said.
"We will certainly work with other labs to identify compounds that can bind to this potential pocket," Tao said. "We can do this computationally. We can screen 50,000 compounds, for example, to see which may bind to the protein with high affinity. Then we can start the optimization procedure."
Co-authors of the paper are former Rice graduate student Liping Dong and Ernesto Méndez, a researcher at the National Autonomous University of Mexico.
The Welch Foundation, the National Institutes of Health and the Kresge Science Initiative Endowment Fund supported the research.
Jade Boyd | EurekAlert!
Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover
First transcription atlas of all wheat genes expands prospects for research and cultivation
17.08.2018 | Leibniz-Institut für Pflanzengenetik und Kulturpflanzenforschung
New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference
Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...
Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...
Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.
When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...
Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.
Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....
Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.
Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...
17.08.2018 | Event News
08.08.2018 | Event News
27.07.2018 | Event News
17.08.2018 | Physics and Astronomy
17.08.2018 | Information Technology
17.08.2018 | Life Sciences