Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain

被引：102

作者：

Lintner, Nathanael G. ^{[1
]}

McClure, Kim F. ^{[2
]}

Petersen, Donna ^{[3
]}

Londregan, Allyn T. ^{[4
]}

Piotrowski, David W. ^{[4
]}

Wei, Liuqing ^{[4
]}

Xiao, Jun ^{[4
]}

Bolt, Michael ^{[5
]}

Loria, Paula M. ^{[3
]}

Maguire, Bruce ^{[3
]}

Geoghegan, Kieran F. ^{[6
]}

Huang, Austin ^{[7
]}

Rolph, Tim ^{[8
]}

Liras, Spiros ^{[2
,4
]}

Doudna, Jennifer A. ^{[1
,9
,10
,11
,12
]}

Dullea, Robert G. ^{[8
]}

Cate, Jamie H. D. ^{[1
,9
,10
,11
]}

机构：

[1] Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA

[2] Pfizer Worldwide Res & Dev, Pfizer Med Chem, Cardiovasc Metab & Endocrine Dis Res Unit, Cambridge, MA USA

[3] Pfizer Worldwide Res & Dev, Primary Pharmacol Grp, Pharmacokinet Dynam & Metab, Groton, CT USA

[4] Pfizer Worldwide Res & Dev, Pfizer Med Chem, Cardiovasc Metab & Endocrine Dis Res Unit, Groton, CT USA

[5] Pfizer Worldwide Res & Dev, Drug Safety Res & Dev, Andover, MA USA

[6] Pfizer Worldwide Res & Dev, Pfizer Med Chem, Struct Biol & Biophys, Groton, CT USA

[7] Pfizer Worldwide Res & Dev, Pfizer Med Chem, Computat Sci, Cambridge, MA USA

[8] Pfizer Worldwide Res & Dev, Cardiovasc Metab & Endocrine Dis Res Unit, Cambridge, MA 02139 USA

[9] Univ Calif Berkeley, Inst QB3, Berkeley, CA 94720 USA

[10] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA

[11] Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA

[12] Univ Calif Berkeley, HHMI, Berkeley, CA 94720 USA

来源：

PLOS BIOLOGY | 2017年 / 15卷 / 03期

基金：

美国国家卫生研究院;

关键词：

NUCLEOTIDE RESOLUTION; IN-VIVO; PCSK9; INITIATION; MECHANISM; REVEALS; ARREST; CELLS; RNA; DIFFERENTIATION;

D O I：

10.1371/journal.pbio.2001882

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 PF06446846 reveals a previously unexpected tunability of the human ribosome that allows small molecules to specifically block translation of individual transcripts.

引用

页数：36

共 56 条

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