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Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions
The biological processes related to protein homeostasis in Mycobacterium tuberculosis, the etiologic agent of tuberculosis, have recently been established as critical pathways for therapeutic intervention. Proteins of particular interest are ClpC1 and the ClpC1–ClpP1–ClpP2 proteasome complex. The st...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
International Union of Crystallography
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193532/ https://www.ncbi.nlm.nih.gov/pubmed/32355042 http://dx.doi.org/10.1107/S2059798320004027 |
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author | Wolf, Nina M. Lee, Hyun Zagal, Daniel Nam, Joo-Won Oh, Dong-Chan Lee, Hanki Suh, Joo-Won Pauli, Guido F. Cho, Sanghyun Abad-Zapatero, Celerino |
author_facet | Wolf, Nina M. Lee, Hyun Zagal, Daniel Nam, Joo-Won Oh, Dong-Chan Lee, Hanki Suh, Joo-Won Pauli, Guido F. Cho, Sanghyun Abad-Zapatero, Celerino |
author_sort | Wolf, Nina M. |
collection | PubMed |
description | The biological processes related to protein homeostasis in Mycobacterium tuberculosis, the etiologic agent of tuberculosis, have recently been established as critical pathways for therapeutic intervention. Proteins of particular interest are ClpC1 and the ClpC1–ClpP1–ClpP2 proteasome complex. The structure of the potent antituberculosis macrocyclic depsipeptide ecumicin complexed with the N-terminal domain of ClpC1 (ClpC1-NTD) is presented here. Crystals of the ClpC1-NTD–ecumicin complex were monoclinic (unit-cell parameters a = 80.0, b = 130.0, c = 112.0 Å, β = 90.07°; space group P2(1); 12 complexes per asymmetric unit) and diffracted to 2.5 Å resolution. The structure was solved by molecular replacement using the self-rotation function to resolve space-group ambiguities. The new structure of the ecumicin complex showed a unique 1:2 (target:ligand) stoichiometry exploiting the intramolecular dyad in the α-helical fold of the target N-terminal domain. The structure of the ecumicin complex unveiled extensive interactions in the uniquely extended N-terminus, a critical binding site for the known cyclopeptide complexes. This structure, in comparison with the previously reported rufomycin I complex, revealed unique features that could be relevant for understanding the mechanism of action of these potential antituberculosis drug leads. Comparison of the ecumicin complex and the ClpC1-NTD-L92S/L96P double-mutant structure with the available structures of rufomycin I and cyclomarin A complexes revealed a range of conformational changes available to this small N-terminal helical domain and the minor helical alterations involved in the antibiotic-resistance mechanism. The different modes of binding and structural alterations could be related to distinct modes of action. |
format | Online Article Text |
id | pubmed-7193532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
spelling | pubmed-71935322020-05-19 Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions Wolf, Nina M. Lee, Hyun Zagal, Daniel Nam, Joo-Won Oh, Dong-Chan Lee, Hanki Suh, Joo-Won Pauli, Guido F. Cho, Sanghyun Abad-Zapatero, Celerino Acta Crystallogr D Struct Biol Research Papers The biological processes related to protein homeostasis in Mycobacterium tuberculosis, the etiologic agent of tuberculosis, have recently been established as critical pathways for therapeutic intervention. Proteins of particular interest are ClpC1 and the ClpC1–ClpP1–ClpP2 proteasome complex. The structure of the potent antituberculosis macrocyclic depsipeptide ecumicin complexed with the N-terminal domain of ClpC1 (ClpC1-NTD) is presented here. Crystals of the ClpC1-NTD–ecumicin complex were monoclinic (unit-cell parameters a = 80.0, b = 130.0, c = 112.0 Å, β = 90.07°; space group P2(1); 12 complexes per asymmetric unit) and diffracted to 2.5 Å resolution. The structure was solved by molecular replacement using the self-rotation function to resolve space-group ambiguities. The new structure of the ecumicin complex showed a unique 1:2 (target:ligand) stoichiometry exploiting the intramolecular dyad in the α-helical fold of the target N-terminal domain. The structure of the ecumicin complex unveiled extensive interactions in the uniquely extended N-terminus, a critical binding site for the known cyclopeptide complexes. This structure, in comparison with the previously reported rufomycin I complex, revealed unique features that could be relevant for understanding the mechanism of action of these potential antituberculosis drug leads. Comparison of the ecumicin complex and the ClpC1-NTD-L92S/L96P double-mutant structure with the available structures of rufomycin I and cyclomarin A complexes revealed a range of conformational changes available to this small N-terminal helical domain and the minor helical alterations involved in the antibiotic-resistance mechanism. The different modes of binding and structural alterations could be related to distinct modes of action. International Union of Crystallography 2020-04-23 /pmc/articles/PMC7193532/ /pubmed/32355042 http://dx.doi.org/10.1107/S2059798320004027 Text en © Wolf et al. 2020 http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Research Papers Wolf, Nina M. Lee, Hyun Zagal, Daniel Nam, Joo-Won Oh, Dong-Chan Lee, Hanki Suh, Joo-Won Pauli, Guido F. Cho, Sanghyun Abad-Zapatero, Celerino Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions |
title | Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions |
title_full | Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions |
title_fullStr | Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions |
title_full_unstemmed | Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions |
title_short | Structure of the N-terminal domain of ClpC1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions |
title_sort | structure of the n-terminal domain of clpc1 in complex with the antituberculosis natural product ecumicin reveals unique binding interactions |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193532/ https://www.ncbi.nlm.nih.gov/pubmed/32355042 http://dx.doi.org/10.1107/S2059798320004027 |
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