PXD023691

PXD023691 is an original dataset announced via ProteomeXchange.

Title	Reprogramming the E3 ubiquitin ligase CRL4CRBN to degrade Helios
Description	The zinc finger transcription factor Helios is critical for maintaining the identity and suppressive phenotype of regulatory T cells (Tregs) and as such is an attractive target to enhance the efficacy of currently approved immunotherapies. However, no small molecules exist which can directly modulate Helios activity or abundance. Here, we report the structure-guided development of novel small molecules capable of inducing neo-interactions between Helios and the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN), thereby promoting Helios degradation. Crystallographic studies reveal that these new compounds accommodate a key histidine residue in the β-hairpin loop of its second zinc finger domain. Finally, pharmacological Helios degradation destabilized the anergic phenotype of regulatory T cells, demonstrating that Helios is a new druggable target that may enhance anti-tumor immunity. Our study provides a road-map for developing small molecule degraders of other difficult-to-drug targets through ligase reprogramming that is complementary to the bi-valent proteolysis targeting chimera (PROTACs) approach.
HostingRepository	PRIDE
AnnounceDate	2021-05-26
AnnouncementXML	Submission_2021-05-25_22:38:09.645.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	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-20 01:36:41	ID requested
⏵ 1	2021-05-25 22:38:10	announced

Dataset with its publication pending

submitter keyword: ubiquitin, molecular glue, imide, helios, CRL4, CRBN, Tregs

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

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PRIDE project URI

• PRIDE
  1. PXD023691
     1. Label: PRIDE project
     2. Name: Reprogramming the E3 ubiquitin ligase CRL4CRBN to degrade Helios