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

ABSTRACT: We use ribosome profiling to demonstrate the selectivity of a small molecule, PF-06446846 that inhibits translation of its target by selectively inducing ribosome-stalling in a nascent chain sequence dependent manner.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94454 | GEO | 2017/06/05

SECONDARY ACCESSION(S): PRJNA369742

REPOSITORIES: GEO

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SECRETOME DATA only from “Selective stalling of human translation through small molecule engagement of the ribosome nascent chain”

Project description:Human genetics as well as pharmacological intervention reveal that 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 stalling the ribosome near codon 34 of its messenger RNA. Inhibition by PF-06446846 is sensitive to the amino acid sequence of the PCSK9 nascent chain, and not the messenger RNA. PF-06446846 also reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling to examine the proteome-wide effects of PF-06446846, we find that it is exceptionally specific for PCSK9 and has no measurable effect on 99.7% of the translatome at concentrations sufficient for 90% inhibition of PCSK9 expression. Together, PF-06446846 represents the first example of an orally administered small molecule directly targeting PCSK9 that functions by a mechanism inhibiting translation during elongation with a high degree of selectivity. Selective inhibition of translation in human may represent a new approach to target proteins with small molecules.

2017-03-27 | PXD005822 | Pride

CELL LYSATE DATA only from “Selective stalling of human translation through small molecule engagement of the ribosome nascent chain”

2017-03-27 | PXD005835 | Pride

Cellular response to small molecules that selectively stall protein synthesis by the ribosome

Project description:We use ribosome profiling to compare the selectivity of two small molecules, PF-06446846 and PF-06378503 that inhibits translation of their target by selectively inducing ribosome-stalling in a nascent chain sequence dependent manner.

2019-03-06 | GSE121981 | GEO

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

Project description: Not available

| S-EPMC5360235 | biostudies-literature

Bacterial ribosome pause sites surveyed by an integration of ribosome profiling and nascent chain profiling

Project description:Ribosome pauses are associated with diverse co-translational events and determine the fate of mRNAs and proteins. Thus the identification of the precise pause sites across transcriptome is a key, however, the landscape in bacterial has remained ambiguous. Here, we harnessed the multiple ribosome profiling strategies (standard, high-salt-wash, and disome) to survey the robust ribosome pause sites in E. coli. The found pause sites showed the correspondence with biochemical validation by integrated nascent chain profiling (iNP), which detects polypeptidyl-tRNA, an elongation intermediate. Among the list, ribosome pause at Asn586 of ycbZ was ensured by biochemical reporter assay, tRNA-seq, and cryo-electron microscopy. Our results provide a useful resource of ribosome stalling sites in bacteria.

2021-11-23 | GSE160623 | GEO

Small Molecule PCSK9 Inhibitors: Hit to lead optimization

Project description:Ribosome profiling is used to demonstrate improved selectivity of compounds that promote PCSK9 translational stalling

2018-06-20 | GSE110426 | GEO

Structural basis for selective stalling of human ribosome nascent chain complexes by a drug-like molecule.

Project description: Not available

| S-EPMC6919564 | biostudies-literature

Bacterial ribosome pause sites surveyed by an integration of ribosome profiling and nascent chain profiling II

2021-11-23 | GSE180482 | GEO

Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration

Project description:In higher eukaryotes, the large numbers of nuclear-encoded tRNA genes partially ensure the robustness of cytoplasmic protein translation. Here we discover that a loss-of-function in n-Tr20, a member of the nuclear-encoded tRNA Arg UCU family that is expressed specifically in the central nervous systems leads to low but detectable levels of ribosome stalling. In the absence of GTPBP2, a novel binding partner of the ribosome recycling protein Pelota, ribosome stalling increases, leading to widespread neurodegeneration. Our results not only define GTPBP2 as a ribosome rescue factor, but also unmask the disease potential of mutations in nuclear-encoded tRNA genes. In this submission we provide ribosome footprinting data from the cerebella of four strains derived from the C57BL/6J strain with combinations of n-Tr20 and GTPBP2 mutations. Examination of ribosome stalling in cerebella from 4 mouse strains derived from the: C57BL/6J (B6J) strain. The nmf205-/- strain has a homozygous mutation in the gene GTPBP2 while the B6J strain has normal GTPBP2. The n-Tr20 J/J strain has a defect in the n-Tr20 tRNA while the n-Tr20 N/N strain has a functional n-Tr20 tRNA. The 4 strains are the 2x2 combinations of these defects and correctly functioning sequences. 2 replicates for each strain. Please note that only BAM files are included in the records since they form the basis of the study's conclusions. The raw data ribosomal RNA have been filtered and then unique reads mapping to mm10 were computed using tophat and igenome annotations.

2014-07-28 | E-GEOD-56127 | biostudies-arrayexpress

Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration

2014-07-28 | GSE56127 | GEO

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