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Publication Abstract from PubMed

Nonribosomal peptide synthetase (NRPS) heterocyclization (Cy) domains generate biologically important ox-/thiazoline groups found in natural products, including pharmaceuticals and virulence factors such as some siderophores. Cy domains catalyze consecutive condensation and cyclodehydration reactions, although the mechanism is unknown. To better understand Cy domain catalysis, here we report the crystal structure of the second Cy domain (Cy2) of yersiniabactin synthetase from the causative agent of the plague, Yersinia pestis. Our high-resolution structure of Cy2 adopts a conformation that enables exploration of interactions with the extended, thiazoline-containing cyclodehydration intermediate and the acceptor carrier protein to which it is tethered. We also report complementary electrostatic interfaces between Cy2 and its donor carrier protein that mediate donor binding. Lastly, we explored domain flexibility through normal mode analysis and identify small-molecule fragment binding sites that may inform future antibiotic design targeting Cy function. Our results suggest how carrier protein binding may influence global Cy conformations, with consequences for active site remodeling to facilitate the separate condensation and cyclodehydration steps as well as potential inhibitor development.

High-resolution structures of a siderophore-producing cyclization domain from Yersinia pestis offer a refined proposal of substrate binding.,Gnann AD, Xia Y, Soule J, Barthelemy C, Mawani JS, Musoke SN, Castellano BM, Brignole EJ, Frueh DP, Dowling DP J Biol Chem. 2022 Sep 2:102454. doi: 10.1016/j.jbc.2022.102454. PMID:36063993^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.