Scientists have discovered something very unusual about a protein that is thought to be important to the development of tuberculosis. They found a very large interior pocket that seems to be able to move things into the cell of the bacterium that causes the disease. Most molecules that move things through a cell membrane, like a channel, are very specific about what they transport, but this one seems to act in a much more generalized way, and can move small and large molecules, and potentially, antibiotics into the cell. While the research may lead to new avenues in tuberculosis prevention or treatment, the researchers are trying to learn more about the purpose of this protein pocket.
"We've never seen anything like this before," said researcher Cornelius Gati, a structural biologist at the Department of Energy's SLAC National Accelerator Laboratory. "It doesn't really make sense." Gait performed the study with collaborators at the University of Groningen, Stockholm University, and the Moscow Institute of Physics and Technology. Their findings were reported in Nature.
Tuberculosis is not a health problem in the United States, but it remains one of the top ten leading causes of death in the world, and is the primary cause of death for people living with HIV.
The bacterium that causes TB, Mycobacterium tuberculosis, is still mysterious. It only causes illness in about one in ten people that it infects, for example, and the reason for that is unknown.
It is known that the bacterium needs to take up vitamin B12 to survive. Gati's team was studying a transporter that had been linked to vitamin B12 shuttling with genetic tools. They used cryo-electron microscopy to learn more about it. "Without this transporter, tuberculosis bacteria cannot survive," Gati said.
Instead of finding a B12 channel, they found a (relatively) huge cavity that's about eight cubic nanometers, which can easily fit several water molecules and perhaps many others including vitamin B12.
"We have seen transporters that move a variety of drugs and molecules out of a cell, with little specificity, but not importers. If this is really an importer that can recognize and import multiple unrelated molecules, that would be fantastic," said Laura Dassama, a chemist at Stanford University and Stanford ChEM-H. It could be a way to get antibiotics into the pathogenic cells.
The researchers have to figure out what can and cannot go into the cavity first, however. They are intrigued and are now trying to find out more about it.