New Ribosome Finding Could Lead to Antiviral Therapies

The ribosome is the protein-producing nanomachine in cells that keeps the human body cranking along. A discovery by University of Maryland researchers has provided a clue that could lead to programming the ribosome to fight viruses like HIV AIDS and SARS.

Ribosomal protein L3 is shown in green. Its fingers extend downward and toward the left into the catalytic core of the ribosome (red). The orange arrow shows the path taken by tRNAs as they travel from outside of the ribosome into its core. Incoming tRNAs must pass through two "gates", shown in yellow. Individual bits of RNA are colored blue to indicate that they are more open or accessible to the outside world when the finger structures of L3 are mutated.

In the March 23 issue of the journal Molecular Cell , University of Maryland biology professor Jonathan Dinman and research assistant professor Artural Meskauskas describe how their discovery of the function of some long protein finger-like structures in the ribosome could lead to new antiviral therapies in the near future.

"One such finger, located in a ribosomal protein called L3, acts as a switch to help the ribosome coordinate all of its functions," said Dinman. "We found that by altering this switch, the cell lost its ability to propagate viruses. If we could mimic this, we could target the L3 protein for antiviral therapies."

Turning Off A Virus

The ribosome is a complex molecular machine that makes proteins, the molecular building blocks of our bodies. "I think of the ribosome as a nanomachine that coordinates events in a sequential order," Dinman said. "The core of the ribosome is made up mostly of RNA, and this does most of the heavy lifting. But the outsides of ribosomes are also decorated with proteins, and these tend to have long tentacle-like structures that extend deep into ribosomal cores."

According to Dinman and Meskauskas's paper, previous studies have shown that L3 plays an important role in a number of cellular functions, including drug resistance and virus replication.

"The finger-like extensions of L3 may help coordinate ribosome-associated functions by acting as a switch or a gatekeeper," Dinman said. "When you alter the L3 switch, you alter the way the ribosome coordinates all of the functions of the cell. We found that the cells with this L3 mutation could not reproduce viruses.

"These mutant forms of L3 also made cells resistant to certain antibiotics. Understanding how these mutants affect the interactions between ribosomes and factors that lead to drug resistance can provide the foundation for design of new antibacterials to counter resistance of pathogens to drugs," said Dinman. "This study also provides a basis for deeper insight into design of small molecule antiviral therapies, hopefully in the near future."

Cartoon of how the switch works Left: This configuration of the L3 finger switch places the ribosome in the "open" position, where it binds the protein that delivers new tRNAs to it (eEF1A-aatRNA-GTP). The tRNAs are then delivered to the ribosomal core in a process called "accommodation". Once there, they participate in the central step of protein synthesis called peptidyltransfer. During this time, the L3 switch moves, closing the ribosome, and forming the binding site for the next player called eEF2-GTP, whose function is to push the ribosome down the mRNA, setting up the next step in the cycle of protein synthesis.

See the article: http://www.cellpress.com/

Cell Press press officer: Heidi Hardman, 617-397-2879, hhardman@cell.com