Schematic Illustration of the Introduction of Cyclic Peptides via Ribosome in a Cell-Free Protein Synthesis System. Credit: POSTECH
Inside our cells, ribosomes—the tireless "protein factories" of life—have just shown off a new skill they haven't used in billions of years. A research team has become the first in the world to successfully expand the range of ring-shaped backbones in proteins using ribosomes, which have traditionally only produced linear backbones.
The breakthrough was recently published in the journal Nature Communications. The study was led by Professor Joongoo Lee in the Department of Chemical Engineering at POSTECH (Pohang University of Science and Technology).
Ribosomes are essential molecular machines found in all living organisms on Earth. Like a master builder snapping together LEGO blocks, they assemble amino acids (tiny molecular components) into the proteins our bodies need. They can join about 20 amino acids per second, a speed tens of thousands of times faster than is achievable through conventional chemical synthesis in a lab.
However, since the dawn of life on Earth, ribosomes have only ever made proteins in a long, noodle-like linear backbone. These linear peptide backbones are relatively fragile and not particularly good at binding to specific targets like viruses, bacteria, or cancer cells, making them less effective as therapeutic drugs. In contrast, ring-shaped backbones are more stable, more durable, and bind more tightly to their targets, but are notoriously difficult and complex to produce chemically.
Inspired by the fact that many natural antibiotics like penicillin contain ring-shaped structures, the POSTECH team asked a bold question: Could ribosomes be coaxed into making these rings themselves?
Cyclic Structures of Natural Products Found in Nature. Credit: POSTECH
Rather than modifying the ribosome itself, the researchers engineered a new set of building blocks, 26 specially designed amino acids. These new amino acids naturally attract each other inside the ribosome, forming rings during the protein-making process.
Using a cell-free protein synthesis system, the team demonstrated that ribosomes could now produce not just linear chains, but also core ring structures such as pentagons and hexagons. Remarkably, these reactions occurred under simple, biological conditions at 37°C and pH 7.5, using the ribosome's original mechanisms, with no external intervention.
This isn't the first time Professor Lee's team has broken new ground. In 2022, in collaboration with Northwestern University and the University of Texas, they were the first to report that ribosomes could be used to create proteins containing six-membered rings; something never before observed in their billions of years of evolutionary history. This new study significantly expands the possibilities, introducing a wider range of materials and demonstrating that ribosomes can now form both five- and six-membered rings.
Even more remarkably, the ring-formation process can be finely controlled by adjusting the design of the special amino acids. The implications are significant. This could open the door to using ribosomes as catalysts for novel chemical reactions, paving the way for next-generation therapeutics and advanced biomaterials.
"What struck me the most," said Professor Lee, "was how similar the reactions inside the ribosome were to the chemical processes we learned in our textbooks. If we can figure out how the ribosome's 4,500 components work together to perform what seems like molecular magic, it could deepen our understanding of both life and evolution."
Provided by Pohang University of Science and Technology