Elevator model for transporting nucleosides inside a cell

Some of the most effective treatments against viral infections and cancer belong to a class of drugs called nucleoside analogs. These are essentially faulty versions of molecular building blocks that can slip into cells and get incorporated into DNA, effectively throwing a wrench into the machinery that viruses and cancer cells to make copies of themselves.

Such compounds, which include chemotherapeutic agents like 5-fluorouracil and gemcitabine, popular HIV drugs like AZT, and potent hepatitis B treatments like acyclovir, have dramatically changed the outcomes for millions of people afflicted with life-threatening illnesses.

Scientists have now modeled the complex shape and movement of biomolecules to make an animation depicting how nucleoside analogs and natural nucleosides are transported into cells. The heart of the system is a specific molecule aptly named the concentrative nucleoside transporter, or CNT. The scientists' movie shows CNT slowly moving its cargo like an elevator, stopping at various points across the cell membrane before reaching the other side.

Their findings, published in Nature, provide important structural information that could be used to design smarter, more specific anticancer and antiviral drugs.

"Our study is the first to provide a visualization of almost every possible conformation of this transporter in motion," said senior study author. "By understanding how this transporter recognizes and imports nucleosides, we may be able to redesign drugs that are better at getting inside specific cells like those harboring cancer or a virus."

Researchers used a technique called x-ray crystallography to create an atomic-level three-dimensional picture of the protein. They then took a series pictures of CNT in different conformations to produce a kind of time-lapse video of the transporter in action: first, as it is ready to capture the nucleoside uridine on the surface of the cell; next, as it moved across the membrane in stages; and finally, as it released the uridine inside the cell.

"We found that there is a region on the protein called the transport domain that acts like an elevator, shifting into different conformations as it transports cargo up and down across the membrane," said the senior author. "Other studies had shown that many transporters move in this way, but ours is the first to record nearly all of the stages of the elevator model. This more detailed understanding could provide a platform to the future development of drugs that are more selective and efficient."

The transporters responsible for importing a variety of different molecules, such as neurotransmitters, metabolites, and ions, use mechanisms similar to CNT. Thus, the new findings could have implications that reach beyond viral infections and cancer to a number of different clinically relevant physiological processes.