PXD007594

PXD007594 is an original dataset announced via ProteomeXchange.

Title	Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation
Description	E3 ubiquitin ligases are key enzymes within the ubiquitin proteasome system which catalyze the ubiquitination of proteins, targeting them for proteasomal degradation. E3 ligases are gaining importance as targets to small molecules, both for direct inhibition and to be hijacked to induce the degradation of non-native neo-substrates using bivalent compounds known as PROTACs (for ‘proteolysis-targeting chimeras’). We describe Homo-PROTACs as an approach to dimerize an E3 ligase to trigger its suicide-type chemical knockdown inside cells. We provide proof-of-concept of Homo-PROTACs using diverse molecules composed of two instances of a ligand for the von Hippel-Lindau (VHL) E3 ligase. The most active compound, CM11, dimerizes VHL with high avidity in vitro and induces potent, rapid and proteasome-dependent self-degradation of VHL in different cell lines, in a highly isoform-selective fashion and without triggering a hypoxic response. This approach offers a novel chemical probe for selective VHL knockdown, and demonstrates the potential for a new modality of chemical intervention on E3 ligases.
HostingRepository	PRIDE
AnnounceDate	2018-10-23
AnnouncementXML	Submission_2018-10-23_15:24:04.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Douglas Lamont
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-08-30 01:00:39	ID requested
⏵ 1	2018-10-23 15:24:05	announced

Maniaci C, Hughes SJ, Testa A, Chen W, Lamont DJ, Rocha S, Alessi DR, Romeo R, Ciulli A, Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation. Nat Commun, 8(1):830(2017) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: E3 ligases

PROTACs

von Hippel-Lindau protein

protein degradation

chemical dimerizers.

Douglas Lamont
contact affiliation	FingerPrints Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, UK
contact email	d.j.lamont@dundee.ac.uk
lab head
Douglas Lamont
contact affiliation	School of Life Sciences
contact email	d.j.lamont@dundee.ac.uk
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/2018/10/PXD007594

PRIDE project URI

• PRIDE
  1. PXD007594
     1. Label: PRIDE project
     2. Name: Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation