Structure of a bound peptide phosphonate reveals the mechanism of nocardicin bifunctional thioesterase epimerase-hydrolase half-reactions

Patel, Ketan D.; d’Andrea, Felipe B.; Gaudelli, Nicole M.; Buller, Andrew R.; Townsend, Craig A.; Gulick, Andrew M.

doi:10.1038/s41467-019-11740-6

Title: Structure of a bound peptide phosphonate reveals the mechanism of nocardicin bifunctional thioesterase epimerase-hydrolase half-reactions

Journal Article · Tue Aug 27 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-11740-6· OSTI ID:1599428

^[1]; d’Andrea, Felipe B. ^[2]; Gaudelli, Nicole M. ^[2]; Buller, Andrew R. ^[2];

^[2];

^[1]

State Univ. of New York (SUNY), Buffalo, NY (United States)
Johns Hopkins Univ., Baltimore, MD (United States)

Nonribosomal peptide synthetases (NRPSs) underlie the biosynthesis of many natural products that have important medicinal utility. Protection of the NRPS peptide products from proteolysis is critical to these pathways and is often achieved by structural modification, principally the introduction of D-amino acid residues into the elongating peptide. These amino acids are generally formed in situ from their L-stereoisomers by epimerization domains or dual-function condensation/epimerization domains. In singular contrast, the thioesterase domain of nocardicin biosynthesis mediates both the effectively complete L- to D-epimerization of its C-terminal amino acid residue (≥100:1) and hydrolytic product release. We report herein high-resolution crystal structures of the nocardicin thioesterase domain in ligand-free form and reacted with a structurally precise fluorophosphonate substrate mimic that identify the complete peptide binding pocket to accommodate both stereoisomers. These structures combined with additional functional studies provide detailed mechanistic insight into this unique dual-function NRPS domain.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source

Sponsoring Organization:: National Institutes of Health (NIH); National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC)

Grant/Contract Number:: AI121072; GM116957; AC02-06CH11357; AC02-98CH10886

OSTI ID:: 1599428

Journal Information:: Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 9 works

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Title: Structure of a bound peptide phosphonate reveals the mechanism of nocardicin bifunctional thioesterase epimerase-hydrolase half-reactions

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