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Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain
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نویسنده
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lintner n.g. ,mcclure k.f. ,petersen d. ,londregan a.t. ,piotrowski d.w. ,wei l. ,xiao j. ,bolt m. ,loria p.m. ,maguire b. ,geoghegan k.f. ,huang a. ,rolph t. ,liras s. ,doudna j.a. ,dullea r.g. ,cate j.h.d.
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منبع
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plos biology - 2017 - دوره : 15 - شماره : 3
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چکیده
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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. © 2017 lintner et al.
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آدرس
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department of molecular and cell biology,university of california,berkeley,berkeley,ca,united states,chemical biology,pfizer worldwide research and development,cambridge,ma, United States, pfizer medicinal chemistry,cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,cambridge,ma, United States, primary pharmacology group,pharmacokinetics,dynamics and metabolism,pfizer worldwide research and development,groton,ct, United States, pfizer medicinal chemistry,cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,groton,ct, United States, pfizer medicinal chemistry,cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,groton,ct, United States, pfizer medicinal chemistry,cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,groton,ct, United States, pfizer medicinal chemistry,cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,groton,ct, United States, drug safety research & development,pfizer worldwide research & development,andover,ma, United States, primary pharmacology group,pharmacokinetics,dynamics and metabolism,pfizer worldwide research and development,groton,ct, United States, primary pharmacology group,pharmacokinetics,dynamics and metabolism,pfizer worldwide research and development,groton,ct, United States, pfizer medicinal chemistry,structural biology and biophysics,pfizer worldwide research and development,groton,ct, United States, pfizer medicinal chemistry,computational sciences,pfizer worldwide research and development,cambridge,ma, United States, cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,cambridge,ma, United States, pfizer medicinal chemistry,cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,cambridge,ma,united states,pfizer medicinal chemistry,cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,groton,ct, United States, department of molecular and cell biology,university of california,berkeley,berkeley,ca,united states,qb3 institute,university of california,berkeley,berkeley,ca,united states,department of chemistry,university of california,berkeley,berkeley,ca,united states,physical biosciences division,lawrence berkeley national laboratory,berkeley,ca,united states,howard hughes medical institute (hhmi),university of california,berkeley,berkeley,ca, United States, cardiovascular,metabolic and endocrine disease research unit,pfizer worldwide research and development,cambridge,ma, United States, department of molecular and cell biology,university of california,berkeley,berkeley,ca,united states,qb3 institute,university of california,berkeley,berkeley,ca,united states,department of chemistry,university of california,berkeley,berkeley,ca,united states,physical biosciences division,lawrence berkeley national laboratory,berkeley,ca, United States
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Authors
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