The protective covering—or nucleocapsid—that Rubella viruses use to sneak into the human body, evade the immune system, and carry out their biological attacks looks nothing like the wrapping of other viruses. Now, for the first time, scientists have determined the structure of the capsid protein that make up Rubella virus’s shell. The structure, the team reports in a new PNAS Early Edition paper, let them see weak spots in the capsid protein’s structure that antiviral drugs could be developed to take advantage of.
“From the structure which we’ve established, we now know exactly where on the capsid protein we’d need to target,” says Michael Rossmann, a biologist at Purdue University and a senior author of the new paper.
Rubella causes “German measles,” a mild disease that becomes particularly dangerous when it affects pregnant women—an infection can cause malformations in a growing fetus. Low-resolution imaging methods, such as electron microscopy, have revealed the overall spherical structure of the viruses. But obtaining structures of the individual protein units that make up the virus’ nucleocapsid has been more difficult.
“The particles appear to be polymorphic; each particle is a little bit different,” explains Rossmann. “This means that the usual methods of obtaining structure by which you average many particles cannot work.”
Rossmann’s group crystalized sections of the capsid protein and was able to obtain three different crystal formations. By looking at each structure separately, they could determine the various 3-dimensional conformations that the protein could adapt.
“The surprising thing was what it wasn’t,” says Rossmann. “It wasn’t like any other capsid protein that’s been seen.”
By combining the data on individual capsid protein structures with the previous data on the overall shape of the Rubella virus, Rossmann and his colleagues could piece together how the capsid proteins assembled into the larger whole—first grouping into pairs, then forming long rows of proteins. By examining how each bit fit together, they could also see which amino acid building blocks of the capsid protein were crucial for assembly.
When the researchers mutated these amino acids in the protein, the nucleocapsid of Rubella virus no longer formed as the virus replicated. “The mutations that stopped assembly of the virus capsid also showed us that when you stop the assembly, you can stop the propagation of the virus,” says Rossmann.
The new structure, Rossmann says, could help researchers design drugs that stop Rubella infections by blocking the virus from assembling its nucleocapsid.
“We know a little bit more about the structure of the Rubella virus capsid proteins and that’s just one step forward in the study of the whole virus,” he says. His lab is now working on determining how the structure of the capsid proteins might be different in the immature forms of the virus.