Structural advances toward understanding the catalytic activity and conformational dynamics of modular nonribosomal peptide synthetases

Covering: up to fall 2022. Nonribosomal peptide synthetases (NRPSs) are a family of modular, multidomain enzymes that catalyze the biosynthesis of important peptide natural products, including antibiotics, siderophores, and molecules with other biological activity. The NRPS architecture involves an assembly line strategy that tethers amino acid building blocks and the growing peptides to integrated carrier protein domains that migrate between different catalytic domains for peptide bond formation and other chemical modifications. Examination of the structures of individual domains and larger multidomain proteins has identified conserved conformational states within a single module that are adopted by NRPS modules to carry out a coordinated biosynthetic strategy that is shared by diverse systems. In contrast, interactions between modules are much more dynamic and do not yet suggest conserved conformational states between modules. Here we describe the structures of NRPS protein domains and modules and discuss the implications for future natural product discovery.

Automated summary

Nonribosomal peptide synthetases (NRPSs) are enzymes that catalyze the biosynthesis of important peptide natural products. The NRPS architecture involves an assembly line strategy that tethers amino acid building blocks and growing peptides. While conserved conformational states have been identified within a single module, interactions between modules are more dynamic. This article describes the structures of NRPS protein domains and modules and discusses their implications for future natural product discovery.