Study provides visualization of different conformations of transporter in motion that may lead to more effective anticancer and antiviral drugs.
Scientists have modeled the shape and movement of biomolecules to depict step-by-step how nucleoside analogs and natural nucleosides are transported into cells.
The findings were published in Nature, and 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 author Seok-Yong Lee, PhD. “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.”
Scientists designed the first nucleoside analogs 50 years ago. Essentially, they are faulty versions of molecular building blocks that can sneak into cells and become incorporated into DNA. Once there, they disrupt the machinery used by viruses and cancer cells to make copies of themselves.
The nucleoside analogues are carried across the cell membrane by nucleoside transporters. In the current study, the investigators sought to capture the concentrative nucleoside transporter (CNT) as it traversed the membrane.
Using X-ray crystallography, the investigators created an atomic-level 3D image of the protein. A serious of pictures were taken of CNT in different conformations to create a time-lapse-like video of the transporter in action.
“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,” Lee said. “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 elevators model. This more detailed understanding could provide a platform to the future development of drugs that are more selective and efficient.”
The transporters, which import a variety of molecules such as neurotransmitters, metabolites, and ions, also use similar mechanisms to CNT, according to the authors. The findings suggest that the information could be used in other clinically relevant physiological processes.