Ebola Protein’s Structure Is Unlike Other Viral Proteins

The new study could help scientists identify drugs able to disrupt the protein's activity.

Jyoti Madhusoodanan, Contributor

(Inside Science) -- The Ebola virus has infected and killed thousands of people in the ongoing epidemic across several countries. Despite its massive impact, the infectious agent responsible is a tiny virus that carries only seven proteins in its genome.

Such small viral genomes are not uncommon, but how the Ebola virus employs this small arsenal to lethal effect is still a mystery. Scientists are working to understand the disease by peering at the structures of these seven proteins, which offer clues to their functions -- and new ways to block their activity with drugs.

One such protein, known as the nucleoprotein because it binds to the virus' RNA, is more abundant than others within Ebola-infected cells and in virus particles. It is also known to be essential to assembling the viral genome and forming new viral particles. Now, scientists have deciphered the structure of a portion of this molecule. Their results, published earlier this year in Acta Crystallographica, found that at least one part of the Ebola nucleoprotein is unlike any previously reported protein structures.

"This is a really important study, because we had no idea what this protein looked like," said Gaya Amarasinghe, a virologist at Washington University in St. Louis who was not involved with the work.

If scientists can decipher a protein's structure, they can then identify drugs able to disrupt its activity.

Previous studies had explained the structure of at least part of five other, less common Ebola proteins. Nucleoproteins from other viruses from the larger family that Ebola belongs to, were also familiar to researchers. But the Ebola virus nucleoprotein remained enigmatic.

Researchers knew that nucleoprotein was made of an unusual string of amino acids, and that it was composed of two parts with separate functions One half functioned to replicate the viral RNA genome, and another appeared important to making the virus’ outer coat. But precisely how these two sections of the protein worked was unknown.

"When you have a protein with a novel amino-acid sequence, you never know if the structure is going to fall into one of the known families or if it's going to be something new," said study author Zygmunt Derewenda, a biophysicist at the University of Virginia in Charlottesville.

To understand the nucleoprotein's structure, Derewenda and his colleagues began by transferring the gene that encodes it into the bacterium E.coli. The bacteria then manufactured both parts of the protein, so the researchers could extract the protein, crystallize and study its 3-dimensional structure.

The structure they identified -- only the nucleoprotein half that helps with making the outer coat of the virus -- included components common to many other proteins, such as alpha-helices, beta-sheets, and several loops connecting these structures. But the arrangement of these structural units was unlike that seen in any previously known protein.

This arrangement of building blocks into a 3-dimensional structure is similar to a musical composition, according to Derewenda.

"There’s a limited number of musical notes, but an almost unlimited number of tunes," he said. "In this particular case we have a very unusual tune in the way these pieces and blocks are put together, and that is the principal feature that makes this novel."

This basic research is important to understanding how Ebola operates once it infects, and, crucially, how to combat it. In future work, Derewenda and his coauthors aim to characterize the other half of Ebola’s nucleoprotein, which works to pack the viral RNA genome into infectious particles. However, they've already begun using their current research to seek new cures for the disease.

Current Ebola therapies such as ZMapp use monoclonal antibodies -- large protein molecules themselves -- to fight the infection. But such therapies are expensive and take time to manufacture. Drugs based on smaller molecules are simpler and easier to produce in large amounts quickly, according to study coauthor Daniel Engel, a molecular virologist at the University of Virginia.

Now that researchers know part of the nucleoprotein’s 3-D shape, they can design small-molecule drugs that fit within its grooves and niches -- literally throwing a molecular wrench into the protein's activity. Without the nucleoprotein, Ebola particles would be unable to replicate and cause disease.

"The small molecule -- if everything works out -- could be administered as a pill and could be dispensed from a local pharmacy, even in regions where access to healthcare is minimal," Engel said. "This is a good example of how a basic research finding leads directly to an idea for how to treat a disease."

Jyoti Madhusoodanan is a science writer based in San Jose, Calif. She tweets at @smjyoti