PXD056867

PXD056867 is an original dataset announced via ProteomeXchange.

Title	Expanding the set of zinc finger proteins accessible to drug-induced protein degradation by CRBN
Description	Glutarimide analogs, including thalidomide, redirect the E3 ubiquitin ligase CRL4CRBN to induce the ubiquitination and proteasomal degradation of specific zinc finger (ZF) proteins. While the core structural motif recognized by CRBN is characterized, it alone does not account for the full specificity of substrate recognition. To understand the impact of residues adjacent to the core motif, we constructed an extended ZF reporter library including all single ZFs and tandem ZF pairs in the human proteome totaling to 9,098 reporters from 1,655 ZF-containing proteins. We screened the activity of 29 glutarimide analogs against this ZF library leading to the identification and validation of compounds that collectively degrade 38 ZF reporters. High resolution cryo-electron microscopy and crystal structures of wild-type and mutant ZFs complexed with CRBN highlighted the significance of contacts outside the core ZF degron. We conducted systematic mutagenesis of both the ZFs and CRBN to investigate the role of individual amino acids and discovered that residues adjacent to the core ZF degron affect degradability, with single amino acid changes dictating drug specificity. Finally, we identified subtle chemical differences between glutarimide analogs that drastically broaden the target scope and redefine target selectivity. This study expands the scope of degradable ZF targets, including disease-driving transcription factors and provides a roadmap for the rational design of glutarimide analogs.
HostingRepository	PRIDE
AnnounceDate	2025-08-08
AnnouncementXML	Submission_2025-08-08_01:02:37.391.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-16 11:27:13	ID requested
⏵ 1	2025-08-08 01:02:37	announced

Dataset with its publication pending

submitter keyword: CRBN, targeted protein degradation, functional genomics, IMiD, zinc finger

Eric Fischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	Eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.edu
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/2025/08/PXD056867

PRIDE project URI

• PRIDE
  1. PXD056867
     1. Label: PRIDE project
     2. Name: Expanding the set of zinc finger proteins accessible to drug-induced protein degradation by CRBN