Many pharmaceutical compounds are derived from nonribosomal peptide synthetase (NRPS) products. Traditional type I NRPSs have multiple enzymatic domains in a single protein, whereas type II NRPSs consist of stand alone enzymes with diverse functionalization properties and partner proteins. In order to engineer NRPSs to control natural product derivatization, we must first obtain a blueprint on the interface of each protein-protein interaction. As a thrust towards the combinatorial biosynthesis of type II NRPSs, this project involves the structural elucidation of the protein-protein interactions between type II peptidyl carrier proteins (PCP) and their cognate adenylation domain (A domain), which are essential NRPS domains. Structural analysis, including nuclear magnetic resonance and x-ray crystallography, on the transient PCP and A domain complex of type II pyrrolyl NRPS systems, reveals an interface that contrasts the interface of recently obtained type I and type II PCP-A domain complex structures. This difference reveals the diversity of PCP and partner protein binding modes across NRPS systems, which adds a layer of complexity in the combinatorial biosynthesis of NRPS systems.

Interface analysis of the pyrrolyl carrier protein and adenylation domain in type II nonribosomal peptide synthetases

2019 Fall National Meeting

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