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Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin
Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite’s cell envelope. Here we determined the atomic resolution electron cryo-microscopy (cryo-EM) structure of...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693986/ https://www.ncbi.nlm.nih.gov/pubmed/29150609 http://dx.doi.org/10.1038/s41467-017-01664-4 |
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author | Shalev-Benami, Moran Zhang, Yan Rozenberg, Haim Nobe, Yuko Taoka, Masato Matzov, Donna Zimmerman, Ella Bashan, Anat Isobe, Toshiaki Jaffe, Charles L. Yonath, Ada Skiniotis, Georgios |
author_facet | Shalev-Benami, Moran Zhang, Yan Rozenberg, Haim Nobe, Yuko Taoka, Masato Matzov, Donna Zimmerman, Ella Bashan, Anat Isobe, Toshiaki Jaffe, Charles L. Yonath, Ada Skiniotis, Georgios |
author_sort | Shalev-Benami, Moran |
collection | PubMed |
description | Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite’s cell envelope. Here we determined the atomic resolution electron cryo-microscopy (cryo-EM) structure of the Leishmania ribosome in complex with paromomycin (PAR), a highly potent compound recently approved for treatment of the fatal visceral leishmaniasis (VL). The structure reveals the mechanism by which the drug induces its deleterious effects on the parasite. We further show that PAR interferes with several aspects of cytosolic translation, thus highlighting the cytosolic rather than the mitochondrial ribosome as the primary drug target. The results also highlight unique as well as conserved elements in the PAR-binding pocket that can serve as hotspots for the development of novel therapeutics. |
format | Online Article Text |
id | pubmed-5693986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56939862017-11-20 Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin Shalev-Benami, Moran Zhang, Yan Rozenberg, Haim Nobe, Yuko Taoka, Masato Matzov, Donna Zimmerman, Ella Bashan, Anat Isobe, Toshiaki Jaffe, Charles L. Yonath, Ada Skiniotis, Georgios Nat Commun Article Leishmania is a single-celled eukaryotic parasite afflicting millions of humans worldwide, with current therapies limited to a poor selection of drugs that mostly target elements in the parasite’s cell envelope. Here we determined the atomic resolution electron cryo-microscopy (cryo-EM) structure of the Leishmania ribosome in complex with paromomycin (PAR), a highly potent compound recently approved for treatment of the fatal visceral leishmaniasis (VL). The structure reveals the mechanism by which the drug induces its deleterious effects on the parasite. We further show that PAR interferes with several aspects of cytosolic translation, thus highlighting the cytosolic rather than the mitochondrial ribosome as the primary drug target. The results also highlight unique as well as conserved elements in the PAR-binding pocket that can serve as hotspots for the development of novel therapeutics. Nature Publishing Group UK 2017-11-17 /pmc/articles/PMC5693986/ /pubmed/29150609 http://dx.doi.org/10.1038/s41467-017-01664-4 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Shalev-Benami, Moran Zhang, Yan Rozenberg, Haim Nobe, Yuko Taoka, Masato Matzov, Donna Zimmerman, Ella Bashan, Anat Isobe, Toshiaki Jaffe, Charles L. Yonath, Ada Skiniotis, Georgios Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin |
title | Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin |
title_full | Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin |
title_fullStr | Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin |
title_full_unstemmed | Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin |
title_short | Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin |
title_sort | atomic resolution snapshot of leishmania ribosome inhibition by the aminoglycoside paromomycin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693986/ https://www.ncbi.nlm.nih.gov/pubmed/29150609 http://dx.doi.org/10.1038/s41467-017-01664-4 |
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