PXD036539

PXD036539 is an original dataset announced via ProteomeXchange.

Title	Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog Pathway Inhibitor-1
Description	Target deconvolution of small molecule hits from phenotypic screens presents a major challenge. Illustrative of these are the many screens that have been conducted to find inhibitors for the Hedgehog (Hh) signaling pathway – a major developmental pathway with many implications in health and disease - with many hits but very few identified cellular targets. We here present a strategy for target identification based on Proteolysis-Targeting Chimeras (PROTACs), combined with label-free quantitative proteomics. We developed a PROTAC based on the downstream Hedgehog Pathway Inhibitor-1 (HPI-1), a phenotypic screen hit with unknown cellular target. Using our Hedgehog Pathway PROTAC (HPP) we identified and validated BET bromodomains to be the cellular targets of HPI-1. Furthermore, we found that HPP-9 has a unique mechanism of action as a long-acting Hh pathway inhibitor through prolonged BET bromodomain degradation. Collectively, we provide a powerful PROTAC-based approach for target deconvolution, that has answered the longstanding question of the cellular target of HPI-1 and yielded the first PROTAC that acts on the Hh pathway.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:03:02.742.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Midy Wu
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-05 10:01:16	ID requested
1	2023-07-20 11:05:44	announced
⏵ 2	2023-11-14 09:03:03	announced	2023-11-14: Updated project metadata.

Bagka M, Choi H, H, é, ritier M, Schwaemmle H, Pasquer QTL, Braun SMG, Scapozza L, Wu Y, Hoogendoorn S, Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1. Nat Commun, 14(1):3893(2023) [pubmed]

submitter keyword: Hedgehog pathway,PROTAC, protein degradation

Yibo Wu
contact affiliation	Facutly of Science, University of Geneva
contact email	wyb0828@gmail.com
lab head
Midy Wu
contact affiliation	RIKEN
contact email	wyb0828@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036539
     1. Label: PRIDE project
     2. Name: Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog Pathway Inhibitor-1