Lasso peptides are short peptides containing an N-terminal macrolactam macrocycle "ring" through which a linear C-terminal "tail" is threaded. Because of this threaded-loop topology, these peptides resemble lassos, giving rise to their name. They are a member of a larger class of amino-acid-based lasso structures. Additionally, lasso peptides are formally rotaxanes.
The N-terminal "ring" can be from 7 to 9 amino acids long and is formed by an isopeptide bond between the N-terminal amine of the first amino acid of the peptide and the carboxylate side chain of an aspartate or glutamate residue. The C-terminal "tail" ranges from 7 to 15 amino acids in length.
The first amino acid of lasso peptides is almost invariably glycine or cysteine, with mutations at this site not being tolerated by known enzymes. Thus, bioinformatics-based approaches to lasso peptide discovery have thus used this as a constraint. However, some lasso peptides were recently discovered that also contain serine or alanine as their first residue.
The threading of the lasso tail is trapped either by disulfide bonds between ring and tail cysteine residues (class I lasso peptides), by steric effects due to bulky residues on the tail (class II lasso peptides), or both (class III lasso peptides). The compact structure makes lasso peptides frequently resistant to proteases or thermal unfolding.