PXD075638

PXD075638 is an original dataset announced via ProteomeXchange.

Title	14-3-3 immunoprecipitation followed by LC-MS in MCF7 cells treated CV2a (PROTAC)
Description	Proteins lacking defined ligandable pockets remain challenging drug targets. Here, we develop a molecular glue-based PROTAC (MGPROTACs) approach that chemically conjugates a molecular glue stabilizer to a VHL-recruiting ligand to capture and ubiquitinate the 14-3-3/Estrogen Receptor α (ERα) complex. Our designed MGPROTACs engage a composite interface between 14-3-3 and the disordered F-domain of ERα, promoting cooperative complex formation and target ubiquitination. Biophysical characterization revealed distinct linker-dependent cooperativities across the MGPROTAC series, which influenced both cellular permeability and ubiquitination efficiency. Cryo-EM of the most cooperative MGPROTAC uncovers de novo VHL–14-3-3ζ contacts, while molecular dynamics simulations rationalize the stabilizing interactions underlying cooperativity. Strikingly, fine-tuning linker design enables selective ubiquitination of distinct complex subunits. These findings establish a structural and mechanistic framework for integrating molecular glue and PROTAC principles, expanding the scope of drug discovery to previously intractable protein complexes.
HostingRepository	PRIDE
AnnounceDate	2026-07-08
AnnouncementXML	Submission_2026-07-08_01:41:51.053.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD075638
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Laura Demmers
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2026-03-13 21:33:32	ID requested
⏵ 1	2026-07-08 01:41:51	announced

10.6019/PXD075638;

10.1038/S41467-026-75333-W;

submitter keyword: 14-3-3, LC-MS, immunoprecipitation, PROTAC

Christian Ottmann
contact affiliation	Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Netherlands
contact email	c.ottmann@tue.nl
lab head
Laura Demmers
contact affiliation	Ambagon Therapeutics
contact email	ldemmers@ambagontx.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/2026/07/PXD075638

PRIDE project URI

• PRIDE
  1. PXD075638
     1. Label: PRIDE project
     2. Name: 14-3-3 immunoprecipitation followed by LC-MS in MCF7 cells treated CV2a (PROTAC)