The conformationally dynamic structural biology of lanthipeptide biosynthesis.

Lanthipeptide synthetases are fascinating biosynthetic enzymes that install intramolecular thioether bridges into genetically encoded peptides, typically endowing the peptide with therapeutic properties. The factors that control the macrocyclic topology of lanthipeptides are numerous and remain difficult to predict and manipulate. The key challenge in this endeavor derives from the vast conformational space accessible to the disordered precursor lanthipeptide, which can be manipulated in subtle ways by interaction with the cognate synthetase. This review explores the unique strategies employed by each of the five phylogenetically divergent classes of lanthipeptide synthetase to manipulate and exploit the dynamic lanthipeptide conformational ensemble, collectively enabling these biosynthetic enzymes to guide peptide maturation along specific trajectories to products with distinct macrocyclic topology and biological activity.