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

Abstract:

: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.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Lintner NG,McClure KF,Petersen D,Londregan AT,Piotrowski DW,Wei L,Xiao J,Bolt M,Loria PM,Maguire B,Geoghegan KF,Huang A,Rolph T,Liras S,Doudna JA,Dullea RG,Cate JH

doi

10.1371/journal.pbio.2001882

subject

Has Abstract

pub_date

2017-03-21 00:00:00

pages

e2001882

issue

3

eissn

1544-9173

issn

1545-7885

pii

pbio.2001882

journal_volume

15

pub_type

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