Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

ABSTRACT: Cereblon (CRBN) is a ubiquitin ligase widely harnessed for targeted protein degradation. We report the discovery of a molecular glue that drives CRBN homo-dimerization and subsequent fast, potent, and selective CRBN degradation by the ubiquitin proteasome system. The structure of the complex reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a protein degron in trans.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Jurkat Cell

SUBMITTER: Despoina Kapsitidou

LAB HEAD: Debora Bonenfant

PROVIDER: PXD060261 | Pride | 2025-09-08

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	PX_DEG_00497_2024_ECL02_MS3_Aurora_Fct.mzML	Mzml
	PX_DEG_00497_2024_ECL02_MS3_Aurora_Fct.mzid	Mzid
	PX_DEG_00497_2024_ECL02_MS3_Aurora_Fct01_0741.raw	Raw
	PX_DEG_00497_2024_ECL02_MS3_Aurora_Fct02_0742.raw	Raw
	PX_DEG_00497_2024_ECL02_MS3_Aurora_Fct03_0743.raw	Raw

Items per page:

1 - 5 of 61

Similar Datasets

A degron-mimicking molecular glue drives CRBN homo-dimerization and degradation

Project description:Cereblon (CRBN) is a ubiquitin ligase widely harnessed for targeted protein degradation. We report the discovery of a molecular glue that drives CRBN homo-dimerization and subsequent fast, potent, and selective CRBN degradation by the ubiquitin proteasome system. The structure of the complex reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a protein degron in trans.

2025-09-08 | PXD065335 | Pride

Discovery of a Small Molecule Degrader that Sustains pan-AKT Degradation and Downstream Signaling Effects

Project description:The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over 50% of tumors showing aberrant AKT hyperactivation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of GDC-0068, an AKT inhibitor, conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase, Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Overall, our findings suggest that AKT degradation may provide prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.

2019-11-27 | PXD015207 | Pride

Interactors of USP7-TRAF domain in rat neurons

Project description:USP7 protein has a TRAF domain near the N-terminus, which has been reported to bind to many substrates of USP7 in cancer cells. Here we looked for interactors of this USP7-TRAF domain in primary rat neurons. We expressed and immunprecipitated the FLAG-tagged USP7-TRAF domain in neurons. We also used the binding-deficient mutant TRAF RDW as negative control. The immunoprecipitated USP7-TRAF along with its interactors were profiled with LC-MS/MS.

2025-02-24 | PXD043225 | Pride

Activity based proteome profiling of serum serine hydrolases: application in pediatric abusive head trauma

Project description:Purpose: Traumatic brain injury (TBI), including pediatric abusive head trauma (AHT), is the leading cause of death and disability in children and young adults worldwide. The current understanding of trauma-induced molecular changes in the brain of human subjects with intracranial haemorrhage (ICH) remains inadequate and requires further investigation to improve the outcome and management of TBI in the clinic. Calcium-mediated damage at the site of brain injury has been shown to activate several catalytic enzymes. Experimental design: Serine hydrolases (SHs) are major catalytic enzymes involved in the biochemical pathways of blood coagulation, systemic inflammation and neuronal signaling. Here we investigated activity-based protein profiling (ABPP) by measuring the activity status of SH enzymes in the serum of infants with severe ICH as a consequence of AHT or atraumatic infants who died of sudden infant death syndrome (SIDS). Results: Our proof-of-principle study revealed significantly reduced physiological activity of dozens of metabolic SHs in the serum of infants with severe AHT compared to the SIDS group, with some of the enzymes being related to neurodevelopment and basic brain metabolism.

2025-06-26 | PXD057319 | Pride

Selective Mitochondrial Respiratory Complex I Subunit Deficiency Causes Tumor Immunogenicity

Project description:Targeting of specific metabolic pathways in tumor cells has the potential to sensitize them to immune-mediated attack. Previous studies had implicated mitochondria as a potential target for cancer therapies. We screen several complex I subunit deletions for their ability to induce an immune dependent anti-tumor response. Proteomic analysis of tumors lacking the complex I subunit NDUFS4 showed an increase in proteins involved in peptide antigen processing and presentation. We determined this increase in protein levels to be driven epigenetically through H3K27 acetylation from mitochondrial derived acetyl-CoA.

2024-10-05 | PXD051275 | Pride

Mouse RNF138 immunoprecipitation mass spectrography analysis in macrophages

Project description:As one of the core components of the SWI/SNF complex, SMARCC1 (BAF155, SRG3) plays essential roles in activation of the late inflammatory genes in response to microbial challenge. However, little is known about the mechanism how SMARCC1 regulates the inflammatory innate response. Via functional screening, we identify nuclear E3 ubiquitin ligase RNF138 as a negative regulator in inflammatory innate response, and show that RNF138 interacts with SMARCC1 and mediates its K48-linked polyubiquitination at position Lys643 and proteasomal degradation. As a result, catalytic activity of RNF138 fine-tunes the kinetics of late inflammatory gene transcription by inhibiting chromatin remodeling at SWI/SNF regulated gene loci. The reduced RNF138 and increased SMARCC1 in monocytes of rheumatoid arthritis patients are observed. These results provide mechanistic insight into the interplay among nucleosome remodeling, inflammation and ubiquitylation, and underscore the important role of the E3 ubiquitin ligases in controlling both extent and duration of inflammatory responses.

2023-01-10 | PXD039333 | Pride

DNAAF9 interactome from human airway epithelial cells

Project description:Biogenesis of motile cilia in multiciliated cells (MCCs) is coupled to large-scale biosynthesis of force generating dynein motors. Shulin inhibits pre-assembled ODA (outer dynein arm) motors by packaging them into a closed conformation preventing aberrant off-target interactions with cellular microtubules in multiciliated Tetrahymena cells and co-localises with them in growing cilia. How packaged ODAs engage the Intraflagellar Transport machinery (IFT) to transit from the cytoplasm into growing cilia remains unclear. The mechanism of Shulin’s release for ODA activation inside cilia is also poorly resolved. Using proteomics, we establish links between DNAAF9 (human Shulin) and mammalian ODAs, the anterograde IFT-B complex and a ciliary small GTPase called ARL3. Based on our findings, we propose that Shulin/DNAAF9 enforces ODA inhibition to aid their unimpeded trafficking from the cytoplasm into growing multicilia via IFT and once inside the ciliary compartment, ARL3-GTP competes for a binding site to destabilise the ODA-Shulin complex thereby promoting ODA motor activation.

2025-07-31 | PXD052722 | Pride

N2 versus octr-1 shotgun proteomics nano MS/MS

Project description:by using a mass spectrometry-based quantitative proteomics approach, we discovered that OCTR-1 regulates innate immunity by suppressing translation and the unfolded protein response (UPR) pathways at the protein level.

2016-12-22 | PXD004173 | Pride

Large-scale characterization of drug-induced changes in thermal stability using proteome-wide thermal shift assays

Project description:In response to an ever-increasing demand of new small molecules therapeutics, numerous chemical and genetic tools have been developed to interrogate compound mechanism of action. Owing to its ability to characterize compound-dependent changes in thermal stability, the proteome-wide thermal shift assay has emerged as a powerful tool in this arsenal. The most recent iterations have drastically improved the overall efficiency of these assays, providing an opportunity to screen compounds at a previously unprecedented rate. Taking advantage of this advance, we quantified 1.498 million thermal stability measurements in response to multiple classes of therapeutic and tool compounds (96 compounds in living cells and 70 compounds in lysates). When interrogating the dataset as a whole, approximately 80% of compounds (with quantifiable targets) caused a significant change in the thermal stability of an annotated target. There was also a wealth of evidence portending off-target engagement despite the extensive use of the compounds in the laboratory and/or clinic. Finally, the combined application of cell- and lysate-based assays, aided in the classification of primary (direct ligand binding) and secondary (indirect) changes in thermal stability. Overall, this study highlights the value of these assays in the drug development process by affording an unbiased and reliable assessment of compound mechanism of action.

2025-02-13 | PXD048009 | Pride

Lysine-specific demethylase 2A enhances binding of various nuclear factors to CpG-rich genomic DNAs by action of its CXXC-PHD domain

Project description:The lysine-specific demethylase 2A gene (KDM2A) is ubiquitously expressed and its transcripts consist of several alternatively spliced forms, including KDM2A and the shorter form N782 that lacks the 3’ end encoding F-box and LRR. KDM2A binds to numerous CpG-rich genomic loci and regulates various cellular activities; however, the mechanism of the pleiotropic function is unknown. Here, we identify the mechanism of KDM2A played by its CXXC-PHD domain. KDM2A is necessary for a rapid proliferation of post-natal keratinocytes while its 3’ end eclipses the stimulatory effect. EGFP-N782 binds to chromatin together with the XRCC5/6 complex, and the CXXC-PHD domain regulates the CpG-rich IGFBPL1 promoter. In vitro, CXXC-PHD enhances binding of nuclear extract ORC3 to the CpG-rich promoter, but not to the AT-rich DIP2B promoter to which ORC3 binds constitutively. Furthermore, CXXC-PHD recruits 94 nuclear factors involved in replication, ribosome synthesis, and mitosis, including POLR1A to the IGFBPL1 promoter. This recruitment is unprecedented; however, the result suggests that these nuclear factors bind to their cognate loci, as substantiated by the result that CXXC-PHD recruits POLR1A to the rDNA promoter. We propose that CXXC-PHD promotes permissiveness for nuclear factors to interact, but involvement of the XRCC5/6 complex in the recruitment is undetermined.

2019-06-28 | PXD012941 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data