Lasso peptides are natural products made by bacteria. Their unusual lasso shape endows them with remarkable stability, protecting them from extreme conditions
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-ChampaignSep 20 2024 . In a new study, published in Nature Chemical Biology, researchers have constructed and tested models for how these peptides are made and demonstrated how this information might be used to advance lasso peptide-based drugs into the clinic.
One rare counterexample is fusilassin cyclase, or FusC, which the Mitchell lab characterized in 2019. Former group members were able to purify the enzyme, and since then, it has served as a model to understand the lasso knot-tying process. Yet, the structure of FusC remained unknown, making it impossible to understand how the cyclase interacts with the peptide to fold the knot.
They also used molecular dynamics simulations to computationally understand how the lasso is folded by the cyclase. "Thanks to the computing power of Folding@home, we were able to collect extensive simulation data to visualize the interactions at the atomic level," said Song Yin, a graduate student in the Shukla lab.
"We also showed that these molecular contacts are the same in several different cyclases across different phyla. Even though we have not tested every system, we believe it's a generalizable model," Barrett said.
Bacteria Cancer Cell Drugs Enzyme Genomic Helix Peptides Ribosome Therapeutics
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