Covering: 1988 to 2012 This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.

A common structural motif consisting of a cystine knot and a small triple‐stranded β‐sheet has been defined from comparison of the 3‐dimensional structures of the polypeptides ω‐conotoxin GVIA (Conus geographus), kalata BI (Oldenlandia affinis DC), and CMTI‐I (Curcurbita maxima). These 3 polypeptides have diverse biological activities and negligible amino acid sequence identity, but each contains 3 disulfide bonds that give rise to a cystine knot. This knot consists of a ring formed by the first 2 bonds (1–4 and 2–5) and the intervening polypeptide backbone, through which the third disulfide (3–6) passes. The other component of this motif is a triple‐stranded, anti‐parallel β‐sheet containing a minimum of 10 residues, XXC₂, XC₅X, XXC₆X (where the numbers on the half‐cystine residues refer to their positions in the disulfide pattern). The presence in these polypeptides of both the cystine knot and antiparallel β‐sheet suggests that both structural features are required for the stability of the motif. This structural motif is also present in other protease inhibitors and a spider toxin. It appears to be one of the smallest stable globular domains found in proteins and is commonly used in toxins and inhibitors that act by blocking the function of larger protein receptors such as ion channels or proteases.