PXD005822

PXD005822 is an original dataset announced via ProteomeXchange.

Title	SECRETOME DATA only from “Selective stalling of human translation through small molecule engagement of the ribosome nascent chain”
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.
HostingRepository	PRIDE
AnnounceDate	2017-03-27
AnnouncementXML	Submission_2017-03-27_01:20:35.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kieran Geoghegan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	6x(13)C labeled residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2017-02-01 01:13:32	ID requested
⏵ 1	2017-03-27 01:20:39	announced

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, Selective stalling of human translation through small-molecule engagement of the ribosome nascent chain. PLoS Biol, 15(3):e2001882(2017) [pubmed]

curator keyword: Biomedical

submitter keyword: PCSK9, translational stalling, SILAC, Huh7 cells, secretome, cell lysate

Kieran Francis Geoghegan
contact affiliation	Pfizer Worldwide Research Groton CT 06340 USA
contact email	kieran.f.geoghegan@pfizer.com
lab head
Kieran Geoghegan
contact affiliation	Pfizer Worldwide Research
contact email	kieran.f.geoghegan@pfizer.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2017/03/PXD005822

PRIDE project URI

• PRIDE
  1. PXD005822
     1. Label: PRIDE project
     2. Name: SECRETOME DATA only from “Selective stalling of human translation through small molecule engagement of the ribosome nascent chain”