Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the s...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-03-01
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| Series: | PLoS Biology |
| Online Access: | http://europepmc.org/articles/PMC5360235?pdf=render |
| _version_ | 1831652563537100800 |
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| author | Nathanael G Lintner Kim F McClure Donna Petersen Allyn T Londregan David W Piotrowski Liuqing Wei Jun Xiao Michael Bolt Paula M Loria Bruce Maguire Kieran F Geoghegan Austin Huang Tim Rolph Spiros Liras Jennifer A Doudna Robert G Dullea Jamie H D Cate |
| author_facet | Nathanael G Lintner Kim F McClure Donna Petersen Allyn T Londregan David W Piotrowski Liuqing Wei Jun Xiao Michael Bolt Paula M Loria Bruce Maguire Kieran F Geoghegan Austin Huang Tim Rolph Spiros Liras Jennifer A Doudna Robert G Dullea Jamie H D Cate |
| author_sort | Nathanael G Lintner |
| collection | DOAJ |
| description | Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts. |
| first_indexed | 2024-12-19T15:48:33Z |
| format | Article |
| id | doaj.art-c8c20b848f9a4b7e848edcb19074a5c8 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-19T15:48:33Z |
| publishDate | 2017-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-c8c20b848f9a4b7e848edcb19074a5c82022-12-21T20:15:16ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852017-03-01153e200188210.1371/journal.pbio.2001882Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain.Nathanael G LintnerKim F McClureDonna PetersenAllyn T LondreganDavid W PiotrowskiLiuqing WeiJun XiaoMichael BoltPaula M LoriaBruce MaguireKieran F GeogheganAustin HuangTim RolphSpiros LirasJennifer A DoudnaRobert G DulleaJamie H D CateProprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts.http://europepmc.org/articles/PMC5360235?pdf=render |
| spellingShingle | Nathanael G Lintner Kim F McClure Donna Petersen Allyn T Londregan David W Piotrowski Liuqing Wei Jun Xiao Michael Bolt Paula M Loria Bruce Maguire Kieran F Geoghegan Austin Huang Tim Rolph Spiros Liras Jennifer A Doudna Robert G Dullea Jamie H D Cate Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biology |
| title | Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. |
| title_full | Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. |
| title_fullStr | Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. |
| title_full_unstemmed | Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. |
| title_short | Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. |
| title_sort | selective stalling of human translation through small molecule engagement of the ribosome nascent chain |
| url | http://europepmc.org/articles/PMC5360235?pdf=render |
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