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Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule
The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific po...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919564/ https://www.ncbi.nlm.nih.gov/pubmed/31160784 http://dx.doi.org/10.1038/s41594-019-0236-8 |
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author | Li, Wenfei Ward, Fred R. McClure, Kim F. Tsai-Lan Chang, Stacey Montabana, Elizabeth Liras, Spiros Dullea, Robert G. Cate, Jamie H. D. |
author_facet | Li, Wenfei Ward, Fred R. McClure, Kim F. Tsai-Lan Chang, Stacey Montabana, Elizabeth Liras, Spiros Dullea, Robert G. Cate, Jamie H. D. |
author_sort | Li, Wenfei |
collection | PubMed |
description | The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyl-tRNA 3’-CCA end is improperly docked in the peptidyl transferase center. Selections of mRNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination, or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest. |
format | Online Article Text |
id | pubmed-6919564 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
spelling | pubmed-69195642019-12-18 Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule Li, Wenfei Ward, Fred R. McClure, Kim F. Tsai-Lan Chang, Stacey Montabana, Elizabeth Liras, Spiros Dullea, Robert G. Cate, Jamie H. D. Nat Struct Mol Biol Article The drug-like molecule PF-06446846 (PF846) binds the human ribosome and selectively blocks the translation of a small number of proteins by an unknown mechanism. In structures of PF846-stalled human ribosome nascent chain complexes, PF846 binds in the ribosome exit tunnel in a eukaryotic-specific pocket formed by 28S ribosomal RNA, and alters the path of the nascent polypeptide chain. PF846 arrests the translating ribosome in the rotated state of translocation, in which the peptidyl-tRNA 3’-CCA end is improperly docked in the peptidyl transferase center. Selections of mRNAs from mRNA libraries using translation extracts reveal that PF846 can stall translation elongation, arrest termination, or even enhance translation, depending on nascent chain sequence context. These results illuminate how a small molecule selectively targets translation by the human ribosome, and provides a foundation for developing small molecules that modulate the production of proteins of therapeutic interest. 2019-06-03 2019-06 /pmc/articles/PMC6919564/ /pubmed/31160784 http://dx.doi.org/10.1038/s41594-019-0236-8 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Li, Wenfei Ward, Fred R. McClure, Kim F. Tsai-Lan Chang, Stacey Montabana, Elizabeth Liras, Spiros Dullea, Robert G. Cate, Jamie H. D. Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule |
title | Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule |
title_full | Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule |
title_fullStr | Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule |
title_full_unstemmed | Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule |
title_short | Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule |
title_sort | structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919564/ https://www.ncbi.nlm.nih.gov/pubmed/31160784 http://dx.doi.org/10.1038/s41594-019-0236-8 |
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