Transient Domain Interactions in Non-Ribosomal Peptide Synthetases

Abstract

Non-ribosomal peptide synthetases (NRPSs) are multi-module, multi-domain enzymes, synthesizing a wealth of important natural products in bacteria and fungi. These products often find pharmaceutical applications as antibiotics, antitumor agents or immunosuppressant drugs. NRPS use a remarkable assembly line organization to covalently load substrates into each module and catalyze peptide bond formation between substrates loaded on adjacent modules. The substrates may optionally be modified by tailoring domains. These multiple catalytic steps require a series of sequential domain interactions, which are currently poorly understood. We have used NMR to study structures and dynamics of NRPS single- and multi-domains. We show that the domains are neither subject to random interactions nor do they display a fixed quaternary organization. Instead, NRPSs are subject to multiple transient domain interactions which are accompanied by a modulation of their internal dynamics. Understanding the dynamic mechanism of NRPS domain communication may open the venue to efficient NRPS assembly line reprogramming and the production of novel pharmaceuticals.View Large Image | View Hi-Res Image | Download PowerPoint Slide