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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...

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Autores principales: Li, Wenfei, Ward, Fred R., McClure, Kim F., Tsai-Lan Chang, Stacey, Montabana, Elizabeth, Liras, Spiros, Dullea, Robert G., Cate, Jamie H. D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
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.
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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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