Structures of two distinct conformations of holo-non-ribosomal peptide synthetases
Abstract
Many important natural products are produced by multidomain non-ribosomal peptide synthetases (NRPSs). During synthesis, intermediates are covalently bound to integrated carrier domains and transported to neighbouring catalytic domains in an assembly line fashion. Understanding the structural basis for catalysis with non-ribosomal peptide synthetases will facilitate bioengineering to create novel products. Here we describe the structures of two different holo-non-ribosomal peptide synthetase modules, each revealing a distinct step in the catalytic cycle. One structure depicts the carrier domain cofactor bound to the peptide bond-forming condensation domain, whereas a second structure captures the installation of the amino acid onto the cofactor within the adenylation domain. These structures demonstrate that a conformational change within the adenylation domain guides transfer of intermediates between domains. Furthermore, one structure shows that the condensation and adenylation domains simultaneously adopt their catalytic conformations, increasing the overall efficiency in a revised structural cycle. Lastly, these structures and the single-particle electron microscopy analysis demonstrate a highly dynamic domain architecture and provide the foundation for understanding the structural mechanisms that could enable engineering of novel non-ribosomal peptide synthetases.
- Authors:
-
- Hauptman-Woodward Medical Research Inst., Buffalo, NY (United States); Univ. at Buffalo, NY (United States)
- Univ. of Minnesota, Minneapolis, MN (United States)
- Univ. of Michigan, Ann Arbor, MI (United States)
- Hauptman-Woodward Medical Research Inst., Buffalo, NY (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE; National Inst. of Health; National Cancer Inst.; National Inst. of General Medical Sciences
- OSTI Identifier:
- 1237742
- Grant/Contract Number:
- AC02-06CH11357; GM-068440; GM-115601; W81XWH-11-2-0218; ACB-12002; AGM-12006
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature (London)
- Additional Journal Information:
- Journal Name: Nature (London); Journal Volume: 529; Journal Issue: 7585; Journal ID: ISSN 0028-0836
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Drake, Eric J., Miller, Bradley R., Shi, Ce, Tarrasch, Jeffrey T., Sundlov, Jesse A., Allen, C. Leigh, Skiniotis, Georgios, Aldrich, Courtney C., and Gulick, Andrew M. Structures of two distinct conformations of holo-non-ribosomal peptide synthetases. United States: N. p., 2016.
Web. doi:10.1038/nature16163.
Drake, Eric J., Miller, Bradley R., Shi, Ce, Tarrasch, Jeffrey T., Sundlov, Jesse A., Allen, C. Leigh, Skiniotis, Georgios, Aldrich, Courtney C., & Gulick, Andrew M. Structures of two distinct conformations of holo-non-ribosomal peptide synthetases. United States. https://doi.org/10.1038/nature16163
Drake, Eric J., Miller, Bradley R., Shi, Ce, Tarrasch, Jeffrey T., Sundlov, Jesse A., Allen, C. Leigh, Skiniotis, Georgios, Aldrich, Courtney C., and Gulick, Andrew M. Wed .
"Structures of two distinct conformations of holo-non-ribosomal peptide synthetases". United States. https://doi.org/10.1038/nature16163. https://www.osti.gov/servlets/purl/1237742.
@article{osti_1237742,
title = {Structures of two distinct conformations of holo-non-ribosomal peptide synthetases},
author = {Drake, Eric J. and Miller, Bradley R. and Shi, Ce and Tarrasch, Jeffrey T. and Sundlov, Jesse A. and Allen, C. Leigh and Skiniotis, Georgios and Aldrich, Courtney C. and Gulick, Andrew M.},
abstractNote = {Many important natural products are produced by multidomain non-ribosomal peptide synthetases (NRPSs). During synthesis, intermediates are covalently bound to integrated carrier domains and transported to neighbouring catalytic domains in an assembly line fashion. Understanding the structural basis for catalysis with non-ribosomal peptide synthetases will facilitate bioengineering to create novel products. Here we describe the structures of two different holo-non-ribosomal peptide synthetase modules, each revealing a distinct step in the catalytic cycle. One structure depicts the carrier domain cofactor bound to the peptide bond-forming condensation domain, whereas a second structure captures the installation of the amino acid onto the cofactor within the adenylation domain. These structures demonstrate that a conformational change within the adenylation domain guides transfer of intermediates between domains. Furthermore, one structure shows that the condensation and adenylation domains simultaneously adopt their catalytic conformations, increasing the overall efficiency in a revised structural cycle. Lastly, these structures and the single-particle electron microscopy analysis demonstrate a highly dynamic domain architecture and provide the foundation for understanding the structural mechanisms that could enable engineering of novel non-ribosomal peptide synthetases.},
doi = {10.1038/nature16163},
journal = {Nature (London)},
number = 7585,
volume = 529,
place = {United States},
year = {Wed Jan 13 00:00:00 EST 2016},
month = {Wed Jan 13 00:00:00 EST 2016}
}
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