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Title: Interdomain and Intermodule Organization in Epimerization Domain Containing Nonribosomal Peptide Synthetases

Abstract

Nonribosomal peptide synthetases are large, complex multidomain enzymes responsible for the biosynthesis of a wide range of peptidic natural products. Inherent to synthetase chemistry is the thioester templated mechanism that relies on protein/protein interactions and interdomain dynamics. Several questions related to structure and mechanism remain to be addressed, including the incorporation of accessory domains and intermodule interactions. The inclusion of nonproteinogenic d-amino acids into peptide frameworks is a common and important modification for bioactive nonribosomal peptides. Epimerization domains, embedded in nonribosomal peptide synthetases assembly lines, catalyze the l- to d-amino acid conversion. Here we report the structure of the epimerization domain/peptidyl carrier protein didomain construct from the first module of the cyclic peptide antibiotic gramicidin synthetase. Both holo (phosphopantethiene post-translationally modified) and apo structures were determined, each representing catalytically relevant conformations of the two domains. The structures provide insight into domain–domain recognition, substrate delivery during the assembly line process, in addition to the structural organization of homologous condensation domains, canonical players in all synthetase modules.

Authors:
 [1];  [1];  [1];  [1]
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  1. Univ. of Florida, Gainesville, FL (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Science Foundation (NSF); USDOE
OSTI Identifier:
1328050
Resource Type:
Accepted Manuscript
Journal Name:
ACS Chemical Biology
Additional Journal Information:
Journal Volume: 11; Journal Issue: 8; Journal ID: ISSN 1554-8929
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES; Interfaces; Peptides and proteins; Monomers; Crystal structure; Chemical structure

Citation Formats

Chen, Wei-Hung, Li, Kunhua, Guntaka, Naga Sandhya, and Bruner, Steven D. Interdomain and Intermodule Organization in Epimerization Domain Containing Nonribosomal Peptide Synthetases. United States: N. p., 2016. Web. doi:10.1021/acschembio.6b00332.
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Chen, Wei-Hung, Li, Kunhua, Guntaka, Naga Sandhya, & Bruner, Steven D. Interdomain and Intermodule Organization in Epimerization Domain Containing Nonribosomal Peptide Synthetases. United States. https://doi.org/10.1021/acschembio.6b00332
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Chen, Wei-Hung, Li, Kunhua, Guntaka, Naga Sandhya, and Bruner, Steven D. Mon . "Interdomain and Intermodule Organization in Epimerization Domain Containing Nonribosomal Peptide Synthetases". United States. https://doi.org/10.1021/acschembio.6b00332. https://www.osti.gov/servlets/purl/1328050.
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@article{osti_1328050,
title = {Interdomain and Intermodule Organization in Epimerization Domain Containing Nonribosomal Peptide Synthetases},
author = {Chen, Wei-Hung and Li, Kunhua and Guntaka, Naga Sandhya and Bruner, Steven D.},
abstractNote = {Nonribosomal peptide synthetases are large, complex multidomain enzymes responsible for the biosynthesis of a wide range of peptidic natural products. Inherent to synthetase chemistry is the thioester templated mechanism that relies on protein/protein interactions and interdomain dynamics. Several questions related to structure and mechanism remain to be addressed, including the incorporation of accessory domains and intermodule interactions. The inclusion of nonproteinogenic d-amino acids into peptide frameworks is a common and important modification for bioactive nonribosomal peptides. Epimerization domains, embedded in nonribosomal peptide synthetases assembly lines, catalyze the l- to d-amino acid conversion. Here we report the structure of the epimerization domain/peptidyl carrier protein didomain construct from the first module of the cyclic peptide antibiotic gramicidin synthetase. Both holo (phosphopantethiene post-translationally modified) and apo structures were determined, each representing catalytically relevant conformations of the two domains. The structures provide insight into domain–domain recognition, substrate delivery during the assembly line process, in addition to the structural organization of homologous condensation domains, canonical players in all synthetase modules.},
doi = {10.1021/acschembio.6b00332},
journal = {ACS Chemical Biology},
number = 8,
volume = 11,
place = {United States},
year = {Mon Jun 13 00:00:00 EDT 2016},
month = {Mon Jun 13 00:00:00 EDT 2016}
}
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Journal Article:
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https://doi.org/10.1021/acschembio.6b00332
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Cited by: 45 works
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Figures / Tables:

Figure 1 Figure 1: Gramicidin S synthetase assembly line. a) Cartoon representation of the NRPS enzymes, GrsA and GrsB. The amino acid building blocks are selected and activated by A domains (adenylation domain, blue, activated amino acid shown in subscript). PCP domains (peptidyl carrier protein, orange) use the 4’-phosphopantethiene, post-translational modification tomore » transport acyl-intermediates. C domains (condensation, green) catalyze peptide bond formation between acyl-S-PCP intermediates of adjacent modules. The E domain (epimerization domain, grey) produces D-phenylalanine (the epimerized stereocenter is highlighted, red) through epimerization at the α-carbon. The di-domain fragment described in this study is shown in an orange box. Gramicidin S b) is released from the termination module by a cyclization reaction of the dimeric pentapeptide catalyzed by the Te domain (thioesterase domain, brown).« less
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