The diverse genus Streptomyces exhibits vast metabolic capacity, producing numerous bioactive secondary metabolites including clinically used antibiotics. Although it is well established that Streptomyces species have developed close beneficial relationships with insects, potential antagonistic interactions are not well understood. In this study, Perrimon, Currie, Dong and colleagues identified an exotoxin that is produced by Streptomyces that specifically kills insects.

Diphtheria toxin comprises three distinct domains: the N-terminal catalytic domain (which is an ADP-ribosyltransferase), a membrane translocation domain and the C-terminal receptor-binding domain. The authors showed that SAIP shares many sequence similarities with diphtheria toxin, including conserved residues within the N-terminal region, which suggests ADP-ribosyltransferase activity. To elucidate the molecular activity of SAIP, the authors solved the crystal structure of the SAIP catalytic domain, which revealed typical features of an ADP-ribosyltransferase, such as several α-helices surrounding a β-sheet and a Q-X-E motif in the active side loop that is important for ribosyltransferase activity. AlphaFold3 prediction of the full-length toxin showed that the three-domain structure is similar to diphtheria toxin.